A flatworm known for its ability to regenerate cells is shedding more light on how cancer could be treated and how regenerative medicine could better target diseases, according to researchers at the University of California, Merced.
In research, biology Professor Néstor Oviedo has shown that signaling by a protein called Target of Rapamycin (TOR) -- found in humans and most other mammals -- is crucial for planaria's unique tissue regeneration. Disabling the protein prevents the flatworm's regrowth, a sign that disabling it in abnormal cells could prevent the growth of a cancer.
"It's a new model in which we can study stem cell behavior by manipulating the signaling pathways," Oviedo said.
Researchers have recognized that the TOR protein plays a role in cancer, aging and degenerative diseases, but they haven't figured out how it works.
Oviedo's lab is approaching this question using tiny flatworms known as planaria. Long relegated as a scientific oddity, the planarian is now among the species that could be crucial in understanding the role of stem cells. The worm's ability to repair itself is unparalleled, and its secrets could help combat cancer and degenerative diseases.
For this study, Oviedo's lab disabled the TOR protein in planaria and then amputated parts of the flatworm. Under typical circumstances, the organism would be able to repair itself.
But researchers discovered the planaria's stem cells recognized they needed to regrow tissue but were unable to regenerate it in the correct place and instead formed tissues in abnormal places. This kind of regeneration hasn't been reported before. Additionally, the planaria with the disabled protein were unable to grow, even if nutrients were available.
In addition to stopping cancer, understanding TOR and its role in regulation could lead to the development of medicines to encourage tissue regeneration and to fight degenerative diseases, such as Alzheimer's.
Graduate student Harshani Peiris, who was the lead author on the paper, said the planaria gives researchers the ability to look at the reactions of an entire organism, rather than just looking at cells in a Petri dish.
"We have a cutting-edge look into what's happening at the system level," Peiris said.
Sunday, April 29, 2012
Saturday, April 28, 2012
HIV 'superinfection' boosts immune response
Women who have been infected by two different strains of HIV from two different sexual partners -- a condition known as HIV superinfection -- have more potent antibody responses that block the replication of the virus compared to women who've only been infected once.
These findings, by researchers at Fred Hutchinson Cancer Research Center in Seattle, are published online March 29 in PLoS Pathogens.
"We found that women who had been infected twice not only had more potent antibody responses, but some of these women had 'elite' antibody activity, meaning that they had a broad and potent ability to neutralize a wide variety of strains of HIV over a sustained period time," said senior author Julie Overbaugh, Ph.D., a member of the Hutchinson Center's Human Biology Division. It is estimated that only about 1 percent of people with HIV are so-called "elite neutralizers" who are able to potently neutralize multiple subtypes of the virus.
"Individuals who become superinfected with a second virus from a different partner represent a unique opportunity for studying the antibody response and may provide insights into the process of developing broad neutralizing antibodies that could inform HIV-vaccine design," she said.
The study suggests that harboring a mixture of different viral strains may be one way to promote a robust antibody response. The findings also suggest that being infected with two different HIV strains not only leads to a strong response, but also a more rapid response that is capable of recognizing many other HIV strains.
The researchers tracked the immune activity of 12 superinfected women from Mombasa, Kenya, over a five-year period and compared each to a control group of three singly infected women. Overbaugh and lead author Valerie Cortez, a doctoral student in her lab, assessed the ability of antibodies present in superinfected and singly infected women to neutralize a spectrum of circulating HIV-1 variants. In doing so they were able to determine whether the presence of two viruses compared to one made a difference in immune response. The researchers controlled for variables such as antibody response prior to superinfection and biomarkers of immunity such as CD4+ T cell count and viral load. The study found that superinfected women had, on average, 1.68 times more neutralizing antibodies than non-superinfected women, and they scored much higher in their ability to neutralize the virus -- superinfected women had 1.46 times greater potency than the singly infected women.
More than 1.1 million Americans are estimated to be living with HIV today, and every nine-and-a-half minutes someone in the U.S. becomes infected, according to the U.S. Department of Health and Human Services. An HIV vaccine is considered the best approach to long-term protection from HIV infection, but attempts to develop such a vaccine so far have meet with limited success.
"The holy grail of an HIV vaccine is to elicit antibodies to the virus because antibodies have been shown to block virus infection. But there has been little progress in determining how to elicit such antibodies with a vaccine. The study of individuals HIV infected who have developed strong antibody responses to the virus may shed light on the best approach to design a vaccine that will induce an effective immune response," Overbaugh said.
These findings, by researchers at Fred Hutchinson Cancer Research Center in Seattle, are published online March 29 in PLoS Pathogens.
"We found that women who had been infected twice not only had more potent antibody responses, but some of these women had 'elite' antibody activity, meaning that they had a broad and potent ability to neutralize a wide variety of strains of HIV over a sustained period time," said senior author Julie Overbaugh, Ph.D., a member of the Hutchinson Center's Human Biology Division. It is estimated that only about 1 percent of people with HIV are so-called "elite neutralizers" who are able to potently neutralize multiple subtypes of the virus.
"Individuals who become superinfected with a second virus from a different partner represent a unique opportunity for studying the antibody response and may provide insights into the process of developing broad neutralizing antibodies that could inform HIV-vaccine design," she said.
The study suggests that harboring a mixture of different viral strains may be one way to promote a robust antibody response. The findings also suggest that being infected with two different HIV strains not only leads to a strong response, but also a more rapid response that is capable of recognizing many other HIV strains.
The researchers tracked the immune activity of 12 superinfected women from Mombasa, Kenya, over a five-year period and compared each to a control group of three singly infected women. Overbaugh and lead author Valerie Cortez, a doctoral student in her lab, assessed the ability of antibodies present in superinfected and singly infected women to neutralize a spectrum of circulating HIV-1 variants. In doing so they were able to determine whether the presence of two viruses compared to one made a difference in immune response. The researchers controlled for variables such as antibody response prior to superinfection and biomarkers of immunity such as CD4+ T cell count and viral load. The study found that superinfected women had, on average, 1.68 times more neutralizing antibodies than non-superinfected women, and they scored much higher in their ability to neutralize the virus -- superinfected women had 1.46 times greater potency than the singly infected women.
More than 1.1 million Americans are estimated to be living with HIV today, and every nine-and-a-half minutes someone in the U.S. becomes infected, according to the U.S. Department of Health and Human Services. An HIV vaccine is considered the best approach to long-term protection from HIV infection, but attempts to develop such a vaccine so far have meet with limited success.
"The holy grail of an HIV vaccine is to elicit antibodies to the virus because antibodies have been shown to block virus infection. But there has been little progress in determining how to elicit such antibodies with a vaccine. The study of individuals HIV infected who have developed strong antibody responses to the virus may shed light on the best approach to design a vaccine that will induce an effective immune response," Overbaugh said.
Dense breasts can nearly double the risk of breast cancer recurrence
Women aged 50 and over with breasts that have a high percentage of dense tissue are at greater risk of their breast cancer recurring, according to Swedish research presented at the eighth European Breast Cancer Conference (EBCC-8) in Vienna on March 21.
Dr Louise Eriksson and her colleagues from the Karolinska Institutet (Stockholm, Sweden) found that women with denser breasts had nearly double the risk of their cancer recurring, either in the same breast or in the surrounding lymph nodes, than women with less dense breasts. They warn that doctors should take breast density into account when making decisions about treatment and follow-up for these women.
When a woman has a mammogram, the resulting scan gives an image of the breast that shows areas of white and black. The white areas represent the dense tissue, made up of the epithelium and stroma [1]. The black areas are made up of fatty tissue, which is not dense. The percentage density (PD) of the breast is calculated by dividing the dense area by the area of the whole breast (dense and non-dense tissue included).
Breast density varies from woman to woman, and it also decreases with age. Dr Eriksson explained: "Density can vary greatly, even between postmenopausal women. In the group of women I studied, those with the lowest percentage density had breasts that were less than one percent dense, whereas those with highest PD had 75-80% dense breasts. The mean average PD was 18%. However, density does decrease with age. Studies have shown a decrease by approximately two percent per year. The largest decrease is seen at menopause when PD decreases by approximately 10%."
The researchers studied the mammograms and outcomes for 1,774 post-menopausal women who were aged 50-74 and who were part of a larger study of all women with breast cancer diagnosed between 1993-1995 in Sweden.
"We found that if you have a PD at diagnosis of 25% or more, you have an almost two-fold increased risk of local recurrence in the breast and surrounding lymph nodes than women with a PD of less than 25%. However, density does not increase the risk of distant metastasis and has no effect on survival. We also see that although mammographic density is one of the strongest risk factors for breast cancer it doesn't seem to influence tumour development in any specific way; for instance, it isn't more associated with oestrogen receptor positive tumours than oestrogen receptor negative tumours, but seems to act as a general stimulator of tumour development," said Dr Eriksson, who is a PhD student at the Karolinska, as well as a physician at the Stockholm South General Hospital.
"Our study shows that breast density before or at diagnosis should be taken into account even after diagnosis, for instance, when deciding on adjuvant treatment and follow-up routines; perhaps women with dense breasts should be followed more frequently or for a longer period of time in order to quickly spot any local recurrence.
"As far as screening programmes are concerned, it is already known that breast density is a risk factor for the occurrence of breast cancer and that it decreases the sensitivity of mammograms. Our study confirms the importance of taking breast density into account in the screening setting."
Until now, little was known about the association between density, tumour characteristics and prognosis once cancer had occurred, and results were conflicting. This study is important because of its size and detailed information on each woman. "This is one of the largest studies to date studying mammographic density, tumour characteristics, and prognosis, including almost 50% of all Swedish breast cancer cases diagnosed 1993-1995," said Dr Eriksson.
Cancer researchers do not know why breast density is a risk factor for breast cancer. "It could simply be due to higher density being associated with more cells, which means that more cells are at risk of developing cancer," she said. "Another hypothesis is that it is the relationship between mammographic density and the stroma (which has been shown to be the main compound of mammographic density) that is central to the increase in risk. There is no leading hypothesis on why an increased amount of stroma would increase breast cancer risk, but it is known that the interaction between the epithelial cells and the stroma is crucial to the development of breast cancer. Based on the results from our study, we propose that mammographic density creates a beneficial environment for epithelial cells to transform into cancer cells; much like fertile soil giving a planted seed the needed nutrients to grow and develop."
Professor David Cameron, from the University of Edinburgh (Edinburgh, UK), and chair of EBCC-8 said: "This study raises questions about how and why the appearance of normal breast tissue on a mammogram could influence the chances of a local recurrence of breast cancer. It is, therefore, more thought-provoking than practice-changing, since it is not clear what a patient, or her physician, should do if the mammogram shows a higher density of the normal breast tissue. A number of factors are known that influence mammographic breast density, but more research is needed to know which of these, if any, is responsible for this important observation."
[1] The breast epithelium is the cellular tissue lining the milk-producing ducts of the breast. The stroma is the supporting cells and connective tissue in the breast.
[2] The study was funded by Märit and Hans Rausing's Initiative against Breast Cancer, the Swedish Research Council, and the Swedish Cancer Society.
Dr Louise Eriksson and her colleagues from the Karolinska Institutet (Stockholm, Sweden) found that women with denser breasts had nearly double the risk of their cancer recurring, either in the same breast or in the surrounding lymph nodes, than women with less dense breasts. They warn that doctors should take breast density into account when making decisions about treatment and follow-up for these women.
When a woman has a mammogram, the resulting scan gives an image of the breast that shows areas of white and black. The white areas represent the dense tissue, made up of the epithelium and stroma [1]. The black areas are made up of fatty tissue, which is not dense. The percentage density (PD) of the breast is calculated by dividing the dense area by the area of the whole breast (dense and non-dense tissue included).
Breast density varies from woman to woman, and it also decreases with age. Dr Eriksson explained: "Density can vary greatly, even between postmenopausal women. In the group of women I studied, those with the lowest percentage density had breasts that were less than one percent dense, whereas those with highest PD had 75-80% dense breasts. The mean average PD was 18%. However, density does decrease with age. Studies have shown a decrease by approximately two percent per year. The largest decrease is seen at menopause when PD decreases by approximately 10%."
The researchers studied the mammograms and outcomes for 1,774 post-menopausal women who were aged 50-74 and who were part of a larger study of all women with breast cancer diagnosed between 1993-1995 in Sweden.
"We found that if you have a PD at diagnosis of 25% or more, you have an almost two-fold increased risk of local recurrence in the breast and surrounding lymph nodes than women with a PD of less than 25%. However, density does not increase the risk of distant metastasis and has no effect on survival. We also see that although mammographic density is one of the strongest risk factors for breast cancer it doesn't seem to influence tumour development in any specific way; for instance, it isn't more associated with oestrogen receptor positive tumours than oestrogen receptor negative tumours, but seems to act as a general stimulator of tumour development," said Dr Eriksson, who is a PhD student at the Karolinska, as well as a physician at the Stockholm South General Hospital.
"Our study shows that breast density before or at diagnosis should be taken into account even after diagnosis, for instance, when deciding on adjuvant treatment and follow-up routines; perhaps women with dense breasts should be followed more frequently or for a longer period of time in order to quickly spot any local recurrence.
"As far as screening programmes are concerned, it is already known that breast density is a risk factor for the occurrence of breast cancer and that it decreases the sensitivity of mammograms. Our study confirms the importance of taking breast density into account in the screening setting."
Until now, little was known about the association between density, tumour characteristics and prognosis once cancer had occurred, and results were conflicting. This study is important because of its size and detailed information on each woman. "This is one of the largest studies to date studying mammographic density, tumour characteristics, and prognosis, including almost 50% of all Swedish breast cancer cases diagnosed 1993-1995," said Dr Eriksson.
Cancer researchers do not know why breast density is a risk factor for breast cancer. "It could simply be due to higher density being associated with more cells, which means that more cells are at risk of developing cancer," she said. "Another hypothesis is that it is the relationship between mammographic density and the stroma (which has been shown to be the main compound of mammographic density) that is central to the increase in risk. There is no leading hypothesis on why an increased amount of stroma would increase breast cancer risk, but it is known that the interaction between the epithelial cells and the stroma is crucial to the development of breast cancer. Based on the results from our study, we propose that mammographic density creates a beneficial environment for epithelial cells to transform into cancer cells; much like fertile soil giving a planted seed the needed nutrients to grow and develop."
Professor David Cameron, from the University of Edinburgh (Edinburgh, UK), and chair of EBCC-8 said: "This study raises questions about how and why the appearance of normal breast tissue on a mammogram could influence the chances of a local recurrence of breast cancer. It is, therefore, more thought-provoking than practice-changing, since it is not clear what a patient, or her physician, should do if the mammogram shows a higher density of the normal breast tissue. A number of factors are known that influence mammographic breast density, but more research is needed to know which of these, if any, is responsible for this important observation."
[1] The breast epithelium is the cellular tissue lining the milk-producing ducts of the breast. The stroma is the supporting cells and connective tissue in the breast.
[2] The study was funded by Märit and Hans Rausing's Initiative against Breast Cancer, the Swedish Research Council, and the Swedish Cancer Society.
Friday, April 27, 2012
Levels of Ki67 in prostate cancer cells reduced by oral Vitamin D supplements
Higher oral doses of plain vitamin D raised levels of calcitriol in prostate tissue. Higher prostate levels of calcitriol, a hormone made from vitamin D, corresponded with lower levels of the proliferation marker Ki67 and increased levels of cancer growth-inhibitory microRNAs in prostate cancer cells, according to data presented at the AACR Annual Meeting 2012, held here March 31 -- April 4.
The results not only point to the mechanisms by which vitamin D affects the rate of prostate cancer growth, but also indicate that vitamin D may slow the growth of prostate cancer cells -- a key finding given that the role of vitamin D in prostate cancer has been "controversial, with some suggesting that higher levels of vitamin D should be avoided," said Reinhold Vieth, Ph.D., professor at the University of Toronto in Toronto, Ontario, Canada.
"This study shows calcitriol makes the foot come off the gas pedal of cancer growth. We are not able to prove that the speed of the car has slowed down, but it certainly is a good sign," said Vieth. "We expect that this early-phase clinical trial will open the door for more detailed clinical research into the usefulness of vitamin D in the treatment or prevention of prostate cancer."
Vieth and colleagues previously reported that in men who were being monitored regularly for prostate cancer, higher vitamin D levels slowed the rate of rise in prostate-specific antigen levels. They randomly assigned 66 men scheduled for radical prostatectomy to daily vitamin D in doses of 400, 10,000 or 40,000 IU for three to eight weeks before surgery.
Researchers found that calcitriol levels in the prostate increased progressively with each daily dose of vitamin D, with 40,000 IU showing the highest levels. These higher levels of calcitriol corresponded with lower prostate levels of Ki67, a protein that indicates prostate cancer cell growth, as well as higher levels of specific growth-inhibitory microRNAs.
Vieth stressed that he and his colleagues do not advocate vitamin D supplementation in doses higher than 4,000 IU daily. Patients were assigned to the 40,000 IU daily dose because of the short presurgical time frame available for study, not as a regular regimen.
"Plain vitamin D provides the raw material to permit the body to take care of its own needs," he said. "We showed here that plain vitamin D allows the prostate to regulate its own level of calcitriol, and at the doses we used, for the time frame we used, it has been safe with the hoped-for desirable outcomes."
The next step in this line of research will be to conduct a phase III clinical trial in which men who are being monitored for prostate cancer progression will be randomly assigned to placebo or to a "high" dose of plain vitamin D.
The results not only point to the mechanisms by which vitamin D affects the rate of prostate cancer growth, but also indicate that vitamin D may slow the growth of prostate cancer cells -- a key finding given that the role of vitamin D in prostate cancer has been "controversial, with some suggesting that higher levels of vitamin D should be avoided," said Reinhold Vieth, Ph.D., professor at the University of Toronto in Toronto, Ontario, Canada.
"This study shows calcitriol makes the foot come off the gas pedal of cancer growth. We are not able to prove that the speed of the car has slowed down, but it certainly is a good sign," said Vieth. "We expect that this early-phase clinical trial will open the door for more detailed clinical research into the usefulness of vitamin D in the treatment or prevention of prostate cancer."
Vieth and colleagues previously reported that in men who were being monitored regularly for prostate cancer, higher vitamin D levels slowed the rate of rise in prostate-specific antigen levels. They randomly assigned 66 men scheduled for radical prostatectomy to daily vitamin D in doses of 400, 10,000 or 40,000 IU for three to eight weeks before surgery.
Researchers found that calcitriol levels in the prostate increased progressively with each daily dose of vitamin D, with 40,000 IU showing the highest levels. These higher levels of calcitriol corresponded with lower prostate levels of Ki67, a protein that indicates prostate cancer cell growth, as well as higher levels of specific growth-inhibitory microRNAs.
Vieth stressed that he and his colleagues do not advocate vitamin D supplementation in doses higher than 4,000 IU daily. Patients were assigned to the 40,000 IU daily dose because of the short presurgical time frame available for study, not as a regular regimen.
"Plain vitamin D provides the raw material to permit the body to take care of its own needs," he said. "We showed here that plain vitamin D allows the prostate to regulate its own level of calcitriol, and at the doses we used, for the time frame we used, it has been safe with the hoped-for desirable outcomes."
The next step in this line of research will be to conduct a phase III clinical trial in which men who are being monitored for prostate cancer progression will be randomly assigned to placebo or to a "high" dose of plain vitamin D.
Thursday, April 26, 2012
Stress management for breast cancer patients may affect disease course
A team of researchers led by Michael H. Antoni, director of the University of Miami's Center for Psycho-Oncology Research, has shown that a stress management program tailored to women with breast cancer can alter tumor-promoting processes at the molecular level. The new study is one of the first to link psychological intervention with genetic expression in cancer patients.
In the study, researchers found that a group-based intervention called Cognitive-Behavioral Stress Management (CBSM) can have an effect on which genes in the cells of the immune system are turned on and off and in ways that may facilitate better recovery during treatment for breast cancer.
"For the women in the CBSM groups, there was better psychological adaptation to the whole process of going through treatment for breast cancer and there were physiological changes that indicated that the women were recovering better," said Antoni, professor of psychology in the College of Arts and Sciences, professor of psychiatry and behavioral sciences, and program leader of biobehavioral oncology at the Sylvester Comprehensive Cancer Center. "The results suggest that the stress management intervention mitigates the influence of the stress of cancer treatment and promotes recovery over the first year."
Previous research has shown that during times of adversity, our nervous and endocrine systems send signals to the immune system, which defends us from disease. In response, our body activates specific genes inside immune cells called white blood cells or leukocytes, Antoni explains.
"For the women who participated in the intervention groups, the genes that signal the production of molecules associated with a healthy immune response, such as type I interferon, were up-regulated -- meaning they were producing more of these substances compared with levels seen in the control group," Antoni said. "At the same time, the genes responsible for the production of substances involved in cancer progression, such as pro-inflammatory cytokines, chemokines, and matrix metalloproteinases were down-regulated."
CBSM is a ten-week group-based program developed at UM that combines relaxation, imagery, and deep breathing, along with cognitive behavior therapy, which is designed to help patients reduce bodily tension, change the way they deal with intrusive stressful thoughts, decrease negative moods, and improve their interpersonal communication skills. In the study, 79 women undergoing primary treatment for stage III breast cancer were randomized into a ten-week CBSM program or a psychoeducational control group in the weeks following surgery. Six-month and 12-month follow-up assessments were conducted.
"You essentially have this timeframe in a woman's life where she is getting diagnosed with breast cancer, followed by surgery, then chemotherapy or radiation, and it's very stressful," Antoni said. "This can be an emotionally and physically exhausting period offering little opportunity for recovery. If stress affects the immune system in a negative way, then their recovery could be slowed down, and those patients taking longer to recover may be at risk for poorer health outcomes. Conversely, if stress management intervention can reduce the impact of stress on the immune system, then recovery may be hastened."
The research team plans to follow the women in this cohort to see if CBSM intervention and its effects on leukocyte gene expression are predictive of recurrence and/or long-term health outcomes.
In the study, researchers found that a group-based intervention called Cognitive-Behavioral Stress Management (CBSM) can have an effect on which genes in the cells of the immune system are turned on and off and in ways that may facilitate better recovery during treatment for breast cancer.
"For the women in the CBSM groups, there was better psychological adaptation to the whole process of going through treatment for breast cancer and there were physiological changes that indicated that the women were recovering better," said Antoni, professor of psychology in the College of Arts and Sciences, professor of psychiatry and behavioral sciences, and program leader of biobehavioral oncology at the Sylvester Comprehensive Cancer Center. "The results suggest that the stress management intervention mitigates the influence of the stress of cancer treatment and promotes recovery over the first year."
Previous research has shown that during times of adversity, our nervous and endocrine systems send signals to the immune system, which defends us from disease. In response, our body activates specific genes inside immune cells called white blood cells or leukocytes, Antoni explains.
"For the women who participated in the intervention groups, the genes that signal the production of molecules associated with a healthy immune response, such as type I interferon, were up-regulated -- meaning they were producing more of these substances compared with levels seen in the control group," Antoni said. "At the same time, the genes responsible for the production of substances involved in cancer progression, such as pro-inflammatory cytokines, chemokines, and matrix metalloproteinases were down-regulated."
CBSM is a ten-week group-based program developed at UM that combines relaxation, imagery, and deep breathing, along with cognitive behavior therapy, which is designed to help patients reduce bodily tension, change the way they deal with intrusive stressful thoughts, decrease negative moods, and improve their interpersonal communication skills. In the study, 79 women undergoing primary treatment for stage III breast cancer were randomized into a ten-week CBSM program or a psychoeducational control group in the weeks following surgery. Six-month and 12-month follow-up assessments were conducted.
"You essentially have this timeframe in a woman's life where she is getting diagnosed with breast cancer, followed by surgery, then chemotherapy or radiation, and it's very stressful," Antoni said. "This can be an emotionally and physically exhausting period offering little opportunity for recovery. If stress affects the immune system in a negative way, then their recovery could be slowed down, and those patients taking longer to recover may be at risk for poorer health outcomes. Conversely, if stress management intervention can reduce the impact of stress on the immune system, then recovery may be hastened."
The research team plans to follow the women in this cohort to see if CBSM intervention and its effects on leukocyte gene expression are predictive of recurrence and/or long-term health outcomes.
Wednesday, April 25, 2012
Diabetes drug appeared to slow prostate cancer growth
The use of metformin in men with prostate cancer before prostatectomy helped to reduce certain metabolic parameters and slow the growth rate of the cancer, according to the results of a phase II study.
Anthony M. Joshua, M.B.B.S., Ph.D., staff medical oncologist at the Princess Margaret Hospital, University Health Network in Toronto, Ontario, Canada, presented the data at the AACR Annual Meeting 2012, held in Chicago March 31 -- April 4.
Metformin is the most commonly prescribed medication for diabetes. Prior laboratory research has suggested that metformin may also help to improve prognosis in patients with prostate cancer by slowing the growth of the cancerous cells.
To follow up on the laboratory clues, Joshua and colleagues evaluated 22 men with confirmed prostate cancer who had been assigned up to 500 mg of metformin three times a day prior to undergoing prostatectomy.
"This gave us the ability to compare what the prostate cancer looked like when it was first diagnosed to what it looked like when the prostate cancer was removed from the body," said Joshua. "We were able to directly measure the effect of metformin on the prostate cancer."
Patients were assigned metformin for a median duration of 41 days. During that time, none of the men reported grade 3 adverse events, and all of them underwent prostatectomy with no adverse effect related to use of metformin.
The researchers found that metformin significantly reduced fasting glucose, insulin growth factor-1, body mass index and waist-to-hip ratio.
In addition, "although these are preliminary results, metformin appeared to reduce the growth rate of prostate cancer in a proportion of men," Joshua said. "Also, it appeared to reduce one of the main growth pathways that may have contributed to the overall growth of the tumor."
These results may have implications for men with prostate cancer who also have diabetes or early undiagnosed diabetes and for men with prostate cancer whose tumors have characteristics that make them sensitive to metformin, according to Joshua.
"This research builds on the hypothesis that metformin has a role in prostate cancer," he said. "Exactly what that role will be will depend on the results of the analysis currently being completed by our study team and others worldwide."
Joshua is particularly interested in better defining the precise mechanism of action and the subpopulation of patients with prostate cancer for whom metformin has the potential to improve outcomes.
Anthony M. Joshua, M.B.B.S., Ph.D., staff medical oncologist at the Princess Margaret Hospital, University Health Network in Toronto, Ontario, Canada, presented the data at the AACR Annual Meeting 2012, held in Chicago March 31 -- April 4.
Metformin is the most commonly prescribed medication for diabetes. Prior laboratory research has suggested that metformin may also help to improve prognosis in patients with prostate cancer by slowing the growth of the cancerous cells.
To follow up on the laboratory clues, Joshua and colleagues evaluated 22 men with confirmed prostate cancer who had been assigned up to 500 mg of metformin three times a day prior to undergoing prostatectomy.
"This gave us the ability to compare what the prostate cancer looked like when it was first diagnosed to what it looked like when the prostate cancer was removed from the body," said Joshua. "We were able to directly measure the effect of metformin on the prostate cancer."
Patients were assigned metformin for a median duration of 41 days. During that time, none of the men reported grade 3 adverse events, and all of them underwent prostatectomy with no adverse effect related to use of metformin.
The researchers found that metformin significantly reduced fasting glucose, insulin growth factor-1, body mass index and waist-to-hip ratio.
In addition, "although these are preliminary results, metformin appeared to reduce the growth rate of prostate cancer in a proportion of men," Joshua said. "Also, it appeared to reduce one of the main growth pathways that may have contributed to the overall growth of the tumor."
These results may have implications for men with prostate cancer who also have diabetes or early undiagnosed diabetes and for men with prostate cancer whose tumors have characteristics that make them sensitive to metformin, according to Joshua.
"This research builds on the hypothesis that metformin has a role in prostate cancer," he said. "Exactly what that role will be will depend on the results of the analysis currently being completed by our study team and others worldwide."
Joshua is particularly interested in better defining the precise mechanism of action and the subpopulation of patients with prostate cancer for whom metformin has the potential to improve outcomes.
New endoscope technology paves the way for 'molecular-guided surgery' for cancer
With more than 15 million endoscope procedures done on patients each year in the U.S. alone, scientists have reported evidence that a new version of these flexible instruments for diagnosing and treating disease shows promise for helping surgeons more completely remove cancerous tumors. Their report on technology that combines the endoscope with the phenomenon responsible for the eerie blue glow in the cooling water of nuclear reactors was part of the 243rd National Meeting & Exposition of the American Chemical Society (ACS).
"The advance marries endoscopes to one of the newest and most exciting fields of medical imaging," said Zhen Cheng, Ph.D., who led the research. "Endoscopes are medical devices consisting of a long, thin, flexible tube of optical fibers fitted with a light and a video camera. Doctors can insert them through natural openings in the body or small surgical incisions to diagnose and treat a wide range of diseases. The new approach expands the use of those fibers to include molecular-guided surgery to remove more of a cancerous tumor than is currently possible."
Conventional endoscopic methods allow doctors to see inside the stomach or colon, for instance, and take biopsy samples for tests. The new imaging technology -- called Cerenkov Luminescence Endoscopy (CLE) -- has advantages over both traditional endoscopic and imaging techniques, like MRI, in also providing information about the functioning of the tissue, Cheng added.
Cheng, who is with Stanford University, explained that CLE relies on the same phenomenon responsible for the soft blue glow in the cooling water in the core of nuclear power reactors. It results from interactions that occur when invisible particles from the nuclear reaction in the core zip through the water faster than the speed of light in water. The glow was named for its discoverer, a Russian scientist, who won the 1958 Nobel Prize.
Cerenkov Luminescence Imaging (CLI) emerged just a few years ago when scientists discovered ways to harness the effect in devices that do not involve nuclear power reactors. Excitement grew when laboratory experiments established that CLI could produce images of organs and guide surgery in laboratory animals to remove remaining cancer cells that otherwise would have been invisible to surgeons. Scientists also found that CLI could dramatically improve the resolution of PET scans, enabling PET scanners to detect smaller objects than previously possible. Cerenkov luminescence was especially exciting because the light used to reveal diseased tissue is visible light that can be detected with simple optical sensors. It also is compatible with commercially available optical imaging instruments and a wide selection of the nuclear imaging agents that doctors use to make structures in the body visible.
"One drawback however, is that the weak blue light -- unlike the X-rays in other medical scans -- barely penetrates through deep tissues," Cheng said. "This limits the usefulness of the technology in humans, where many tumors develop in areas deep inside the body. Our marriage of Cerenkov luminescence with the endoscope may be the perfect solution. With endoscopy, we can get close enough to the diseased tissue to take advantage of this technology."
Cheng pointed out that CLE's transition from laboratory to operating room, which may occur during the next few years, should be relatively smooth because of its similarity to traditional endoscopy. "Since the CLE system is an upgraded version of endoscopy, it is highly compatible with conventional endoscopic imaging requirements," he said.
"The advance marries endoscopes to one of the newest and most exciting fields of medical imaging," said Zhen Cheng, Ph.D., who led the research. "Endoscopes are medical devices consisting of a long, thin, flexible tube of optical fibers fitted with a light and a video camera. Doctors can insert them through natural openings in the body or small surgical incisions to diagnose and treat a wide range of diseases. The new approach expands the use of those fibers to include molecular-guided surgery to remove more of a cancerous tumor than is currently possible."
Conventional endoscopic methods allow doctors to see inside the stomach or colon, for instance, and take biopsy samples for tests. The new imaging technology -- called Cerenkov Luminescence Endoscopy (CLE) -- has advantages over both traditional endoscopic and imaging techniques, like MRI, in also providing information about the functioning of the tissue, Cheng added.
Cheng, who is with Stanford University, explained that CLE relies on the same phenomenon responsible for the soft blue glow in the cooling water in the core of nuclear power reactors. It results from interactions that occur when invisible particles from the nuclear reaction in the core zip through the water faster than the speed of light in water. The glow was named for its discoverer, a Russian scientist, who won the 1958 Nobel Prize.
Cerenkov Luminescence Imaging (CLI) emerged just a few years ago when scientists discovered ways to harness the effect in devices that do not involve nuclear power reactors. Excitement grew when laboratory experiments established that CLI could produce images of organs and guide surgery in laboratory animals to remove remaining cancer cells that otherwise would have been invisible to surgeons. Scientists also found that CLI could dramatically improve the resolution of PET scans, enabling PET scanners to detect smaller objects than previously possible. Cerenkov luminescence was especially exciting because the light used to reveal diseased tissue is visible light that can be detected with simple optical sensors. It also is compatible with commercially available optical imaging instruments and a wide selection of the nuclear imaging agents that doctors use to make structures in the body visible.
"One drawback however, is that the weak blue light -- unlike the X-rays in other medical scans -- barely penetrates through deep tissues," Cheng said. "This limits the usefulness of the technology in humans, where many tumors develop in areas deep inside the body. Our marriage of Cerenkov luminescence with the endoscope may be the perfect solution. With endoscopy, we can get close enough to the diseased tissue to take advantage of this technology."
Cheng pointed out that CLE's transition from laboratory to operating room, which may occur during the next few years, should be relatively smooth because of its similarity to traditional endoscopy. "Since the CLE system is an upgraded version of endoscopy, it is highly compatible with conventional endoscopic imaging requirements," he said.
Tuesday, April 24, 2012
Scientists identify novel pathway for T-cell activation in leprosy
UCLA researchers pinpointed a new mechanism that potently activates T-cells, the group of white blood cells that play a major role in fighting infections.
Published March 25 online in Nature Medicine, the team specifically studied how dendritic cells, immune cells located at the site of infection, become more specialized to fight the leprosy pathogen known as Mycobacterium leprae. Dendritic cells, like scouts in the field of a military operation, deliver key information about an invading pathogen that helps activate the T-cells in launching a more effective attack.
It was previously known that dendritic cells were important for a strong immune response and the number of such cells at an infection site positively correlated with a robust reaction. However, until now it was poorly understood how dendritic cells become more specialized to address specific types of infections.
The researchers found that a protein called NOD2 triggers a cell-signaling molecule called interleukin-32 that induces general immune cells called monocytes to become specialized information-carrying dendritic cells.
"This is the first time that this potent infection-fighting pathway with dendritic cells has been identified, and demonstrated to be important in fighting human disease," said the study's first author Mirjam Schenk, postdoctoral scholar, division of dermatology, David Geffen School of Medicine at UCLA.
In conducting the study, scientists used monocytes taken from the blood of healthy donors and leprosy patients and incubated the cells with the pathogen M. Leprae or specific parts of the mycobacteria, known to trigger NOD2 and TLR2, both associated with immune system activation.
Scientists wanted to investigate how these proteins might trigger mechanisms that turn on different immune receptors that recognize specific parts of the microbe in an infection. The NOD2 interleukin-32 pathway was the most effective and caused monocytes to develop into dendritic cells that carry critical information about the pathogen to the T-cells.
The team studied the gene expression profiles of the protein-triggered pathways and then also examined how the monocytes of leprosy patients responded to NOD2. Scientists found that NOD2 worked to induce moncytes to dendritic cells in tuberloid leprosy, a milder infection that is more easily contained. The NOD2 pathway was inhibited and could not be activated in lepromatous leprosy, which is more serious and causes widespread infection throughout the body.
"We were surprised to find the high potency of the dendritic cells in triggering certain specific T-cell responses, which may be useful in developing new therapeutic strategies for infectious diseases and cancer," said senior investigator Dr. Robert Modlin, UCLA's Klein Professor of Dermatology and chief of dermatology at the Geffen School of Medicine.
Leprosy, one of the world's oldest known diseases, is a chronic infectious disease that affects the skin, the peripheral nerves, the upper respiratory tract and the eyes and can lead to disfigurement of the hands, face and feet. In 2008, approximately 249,000 new cases of leprosy were reported worldwide, according to the World Health Organization.
Modlin adds that leprosy is a good model to study immune mechanisms in host defense since it presents as a clinical spectrum that correlates with the level and type of immune response of the pathogen.
The next stage of research will involve trying to further understand how to manipulate the innate immune system to induce a potent immune response in human infections and possibly for cancer immunotherapy as well.
Published March 25 online in Nature Medicine, the team specifically studied how dendritic cells, immune cells located at the site of infection, become more specialized to fight the leprosy pathogen known as Mycobacterium leprae. Dendritic cells, like scouts in the field of a military operation, deliver key information about an invading pathogen that helps activate the T-cells in launching a more effective attack.
It was previously known that dendritic cells were important for a strong immune response and the number of such cells at an infection site positively correlated with a robust reaction. However, until now it was poorly understood how dendritic cells become more specialized to address specific types of infections.
The researchers found that a protein called NOD2 triggers a cell-signaling molecule called interleukin-32 that induces general immune cells called monocytes to become specialized information-carrying dendritic cells.
"This is the first time that this potent infection-fighting pathway with dendritic cells has been identified, and demonstrated to be important in fighting human disease," said the study's first author Mirjam Schenk, postdoctoral scholar, division of dermatology, David Geffen School of Medicine at UCLA.
In conducting the study, scientists used monocytes taken from the blood of healthy donors and leprosy patients and incubated the cells with the pathogen M. Leprae or specific parts of the mycobacteria, known to trigger NOD2 and TLR2, both associated with immune system activation.
Scientists wanted to investigate how these proteins might trigger mechanisms that turn on different immune receptors that recognize specific parts of the microbe in an infection. The NOD2 interleukin-32 pathway was the most effective and caused monocytes to develop into dendritic cells that carry critical information about the pathogen to the T-cells.
The team studied the gene expression profiles of the protein-triggered pathways and then also examined how the monocytes of leprosy patients responded to NOD2. Scientists found that NOD2 worked to induce moncytes to dendritic cells in tuberloid leprosy, a milder infection that is more easily contained. The NOD2 pathway was inhibited and could not be activated in lepromatous leprosy, which is more serious and causes widespread infection throughout the body.
"We were surprised to find the high potency of the dendritic cells in triggering certain specific T-cell responses, which may be useful in developing new therapeutic strategies for infectious diseases and cancer," said senior investigator Dr. Robert Modlin, UCLA's Klein Professor of Dermatology and chief of dermatology at the Geffen School of Medicine.
Leprosy, one of the world's oldest known diseases, is a chronic infectious disease that affects the skin, the peripheral nerves, the upper respiratory tract and the eyes and can lead to disfigurement of the hands, face and feet. In 2008, approximately 249,000 new cases of leprosy were reported worldwide, according to the World Health Organization.
Modlin adds that leprosy is a good model to study immune mechanisms in host defense since it presents as a clinical spectrum that correlates with the level and type of immune response of the pathogen.
The next stage of research will involve trying to further understand how to manipulate the innate immune system to induce a potent immune response in human infections and possibly for cancer immunotherapy as well.
Monday, April 23, 2012
Rearchers provides insights for treatments of brain disease by tracking protiens behaving badly
A research team led by the University of Melbourne has developed a novel technique that tracks diseased proteins behaving badly by forming clusters in brain diseases such as Huntington's and Alzheimer's.
The technique recently published in Nature Methods is the first of its kind to rapidly identify and track the location of diseased proteins inside cells and could provide insights into improved treatments for brain diseases and others such as cancer.
Developed by Dr Danny Hatters and his team of the Department of Biochemistry and Molecular Biology at the Bio21 Institute, University of Melbourne, the technique uses a flow cytometer to track the protein clusters in cells at a rate of 1000s per minute. In addition, cells with clustered proteins can be recovered for further study -- neither of which had been possible before.
"Being able to identify locations of diseased proteins in cells enables drugs to be developed to target different stages of disease development," he said.
He said the technique has application to many neurological diseases, which are characterized by formations of proteins clustering such as in Alzheimer's, Parkinson's and Huntington's diseases.
"A challenge for researchers has been trying to understand how proteins cluster and cause damage in diseases like Huntington's and Alzheimer's. This is the first approach which could enable us to answer those questions."
"Now we can see how the proteins form clusters inside a cell and can examine which cell functions are being damaged at different steps of the clustering process."
"No drugs at this stage can stop the clustering process in Huntington's disease for example. This sets up platforms to develop drugs that block the formation of clusters," Dr Hatters said.
The technique can also be used to examine how signaling processes occur such as when genes are switched on and off.
"It has application to track events of abnormal gene signaling such as in cancer " Dr Hatters said.
"This technique offers hope in improving treatments for a range of neurological and other conditions," he said.
The technique recently published in Nature Methods is the first of its kind to rapidly identify and track the location of diseased proteins inside cells and could provide insights into improved treatments for brain diseases and others such as cancer.
Developed by Dr Danny Hatters and his team of the Department of Biochemistry and Molecular Biology at the Bio21 Institute, University of Melbourne, the technique uses a flow cytometer to track the protein clusters in cells at a rate of 1000s per minute. In addition, cells with clustered proteins can be recovered for further study -- neither of which had been possible before.
"Being able to identify locations of diseased proteins in cells enables drugs to be developed to target different stages of disease development," he said.
He said the technique has application to many neurological diseases, which are characterized by formations of proteins clustering such as in Alzheimer's, Parkinson's and Huntington's diseases.
"A challenge for researchers has been trying to understand how proteins cluster and cause damage in diseases like Huntington's and Alzheimer's. This is the first approach which could enable us to answer those questions."
"Now we can see how the proteins form clusters inside a cell and can examine which cell functions are being damaged at different steps of the clustering process."
"No drugs at this stage can stop the clustering process in Huntington's disease for example. This sets up platforms to develop drugs that block the formation of clusters," Dr Hatters said.
The technique can also be used to examine how signaling processes occur such as when genes are switched on and off.
"It has application to track events of abnormal gene signaling such as in cancer " Dr Hatters said.
"This technique offers hope in improving treatments for a range of neurological and other conditions," he said.
Sunday, April 22, 2012
Scientists unlock cancer cell death mystery
An international team of scientists has announced a new advance in the ability to target and destroy certain cancer cells. A group led by the University of Leicester has shown that particular cancer cells are especially sensitive to a protein called p21. This protein usually forces normal and cancer cells to stop dividing but it was recently shown that in some cases it can also kill cancer cells.
However, scientists have been unclear about how this happens.
Researcher Salvador Macip, from the University of Leicester Department of Biochemistry, said: "If we could harness this 'killing power' that p21 has, we could think of designing new therapies aimed at increasing its levels in tumours. This is what motivated us to look into it."
Now the team from the universities of Leicester and Cardiff in the UK, University of South Carolina, USA and Karolinska Institutet, Sweden has discovered that cells from sarcomas tend to die in response to p21 and that this is determined by the sensitivity of their mitochondria to oxidants.
They have published their findings in The Journal of Biological Chemistry. The research was funded by the MRC, the NIH, CONACYT and the Swedish Cancer Society.
Dr Macip added: "Our research also showed that p21 can kill cells even in the absence of p53, a protein that is in the main responsible for cell death but is inactivated in most cancers.
"This shows that certain types of cancer, sarcomas for instance, but maybe also others, should respond well to drugs that increase the levels of p21, even if they don't have an active p53. The side effects of these therapies should be minimal, since our experiments show that normal cells would arrest but not die in response to p21.
"There are already drugs available that selectively increase p21. Our results provide a rationale for testing them in certain types of cancers, which could be identified using the experiments we describe."
However, scientists have been unclear about how this happens.
Researcher Salvador Macip, from the University of Leicester Department of Biochemistry, said: "If we could harness this 'killing power' that p21 has, we could think of designing new therapies aimed at increasing its levels in tumours. This is what motivated us to look into it."
Now the team from the universities of Leicester and Cardiff in the UK, University of South Carolina, USA and Karolinska Institutet, Sweden has discovered that cells from sarcomas tend to die in response to p21 and that this is determined by the sensitivity of their mitochondria to oxidants.
They have published their findings in The Journal of Biological Chemistry. The research was funded by the MRC, the NIH, CONACYT and the Swedish Cancer Society.
Dr Macip added: "Our research also showed that p21 can kill cells even in the absence of p53, a protein that is in the main responsible for cell death but is inactivated in most cancers.
"This shows that certain types of cancer, sarcomas for instance, but maybe also others, should respond well to drugs that increase the levels of p21, even if they don't have an active p53. The side effects of these therapies should be minimal, since our experiments show that normal cells would arrest but not die in response to p21.
"There are already drugs available that selectively increase p21. Our results provide a rationale for testing them in certain types of cancers, which could be identified using the experiments we describe."
First Volume Of The Cancer Cell Line Encyclopedia Made Public
The goal of cancer treatment is to match the right drug to the right target in the right patient. But before such "personalized" drugs can be developed, more knowledge is needed about specific genomic alterations in cancers and their sensitivity to potential therapeutic agents.
Now an academic-industry collaboration is releasing the first results from a new and freely available resource that marries deeply detailed cancer genome data with predictors of drug response, information that could lead to refinements in cancer clinical trials and future treatments. The Cancer Cell Line Encyclopedia (CCLE), authored by scientists at the Broad Institute, Dana-Farber Cancer Institute, the Genomics Institute of the Novartis Foundation, and the Novartis Institutes for Biomedical Research, is described in the March 29 issue of the journal Nature. In a proof of principle, the researchers also report that genomic predictors of drug sensitivity revealed three novel candidate biomarkers of response.
"We hope that the Cancer Cell Line Encyclopedia will be a preclinical resource that could guide clinical trials," said Levi A. Garraway, a senior associate member of the Broad Institute, an associate professor at Dana-Farber Cancer Institute and Harvard Medical School, and a co-corresponding author of the paper.
"The CCLE is a public resource that we think will catalyze discoveries throughout the cancer research community," said Todd Golub, director of the Broad's Cancer Program, Charles A. Dana Investigator in Human Cancer Genetics at the Dana-Farber Cancer Institute, and a co-author of the paper. "With this initial effort, we have taken some critical first steps. The challenge now is to greatly expand the number of compounds tested across the panel of cell lines."
The CCLE integrates gene expression, chromosomal copy number, and massively parallel sequencing data from almost 1,000 human cancer cell lines together with pharmacological profiles for 24 anticancer drugs across roughly half of these cell lines. The scale of the project allows greater depth of genetic characterization and pharmacological annotation than previously possible with fewer cell lines. A separate effort by scientists at Massachusetts General Hospital and the Sanger Institute appears in the same issue of Nature.
To accomplish such a feat, the team of scientists relied on the genetics, computational biology, and drug-screening capabilities at the Broad, Dana-Farber, and Novartis. They chose 947 of the nearly 1,200 commercially available cancer cell lines to reflect the genomic diversity of human cancers.
"One of the strengths of the CCLE lies in the number of cell lines it surveys," said Nicolas Stransky, a computational biologist in the Cancer Program at the Broad and a co-first author of the paper. "We can focus on rare cancer subtypes and still have sufficient statistical power for analyses."
Cancer cell lines are malignant cells that have been removed from tumor tissue and cultured in the laboratory. Under controlled conditions, they can grow indefinitely. This near-immortality is an advantage for performing repeated experiments, but it can be a potential pitfall if the cells differ markedly from tumors because they lack typical surroundings. However, with relatively few exceptions, the CCLE cell lines proved to be representative genetic proxies for primary tumor subsets across multiple different cancer types.
Correlating the more than 50,000 genetic and molecular features that emerged from these cell lines created a computational challenge that the scientists met by adapting algorithms to the biological data. They tested this tool against genetic alterations known to predict sensitivity to cancer drugs, and confirmed the value of their systematic approach. Then they applied the predictive modeling methodology to genetic subtypes of cancer known to pose challenges for current treatment modalities.
For example, a variety of cancers have mutations in the NRAS gene, which activates signaling pathways important in tumor growth. Some NRAS-mutant cancers, including a subset of melanomas, may prove vulnerable to drugs that block a protein also involved in signaling, called MEK. The scope of the CCLE enabled the investigators to study approximately 40 cancer cell lines with this mutation to see if they could predict sensitivity to MEK inhibitor drugs, some of which are being studied in clinical trials.
One of the genetic features that rose to the top of their analysis was expression of the aryl hydrocarbon receptor (AHR) gene in cell lines that were highly sensitive to MEK inhibitors. This suggested that high levels of AHR may indicate higher sensitivity to MEK inhibitor drugs. Additional experiments suggested that some of these same cell lines might also depend on AHR activity, and that MEK inhibitors might simultaneously intercept AHR function in some instances.
Armed with this kind of knowledge from the CCLE, researchers may have a much clearer idea of which tumors are most likely to respond to particular drugs before using them in clinical trials, the scientists say. Patients could therefore be selected for such studies based on how likely they are to respond, given the genetic and molecular makeup of their cancers.
"Knowing that kind of information very early might help to improve the success rate of drug development, compared to a genetically 'agnostic' approach that includes any patient with advanced cancer without knowledge of a genetic profile," said Garraway.
The scientists also found new predictors of sensitivity to existing chemotherapy drugs in other cancer cell lines. Elevated levels of SLFN11 expression predicted sensitivity to topoisomerase inhibitors. Another analysis indicates that multiple myeloma may respond to IGF1 receptor inhibitors. Formal clinical studies will be required to learn if these features will hold true in patients.
"We can ask questions not only about emerging targeted therapies, but also about standard chemotherapy drugs," Garraway said. "There may be ways to identify patients who are more likely to respond to conventional chemotherapy versus those who might not. The predicted 'non-responders' may be better off trying a different regimen."
There are more volumes to be written in this encyclopedia.
"From a computational biology perspective, it's a clean, complex data set that allows many more analyses," Stransky said. "We are only scratching the surface of what can be done."
In the CCLE's next phase, analyses based on deeper sequencing, profiles of metabolic activity, and epigenetic modifications - changes in chromatin organization - will also be added.
"This is really the tip of the iceberg," Garraway said. "With these predictive modeling algorithms and with data sets of this size, their study could become an entire discipline in its own right. "
Now an academic-industry collaboration is releasing the first results from a new and freely available resource that marries deeply detailed cancer genome data with predictors of drug response, information that could lead to refinements in cancer clinical trials and future treatments. The Cancer Cell Line Encyclopedia (CCLE), authored by scientists at the Broad Institute, Dana-Farber Cancer Institute, the Genomics Institute of the Novartis Foundation, and the Novartis Institutes for Biomedical Research, is described in the March 29 issue of the journal Nature. In a proof of principle, the researchers also report that genomic predictors of drug sensitivity revealed three novel candidate biomarkers of response.
"We hope that the Cancer Cell Line Encyclopedia will be a preclinical resource that could guide clinical trials," said Levi A. Garraway, a senior associate member of the Broad Institute, an associate professor at Dana-Farber Cancer Institute and Harvard Medical School, and a co-corresponding author of the paper.
"The CCLE is a public resource that we think will catalyze discoveries throughout the cancer research community," said Todd Golub, director of the Broad's Cancer Program, Charles A. Dana Investigator in Human Cancer Genetics at the Dana-Farber Cancer Institute, and a co-author of the paper. "With this initial effort, we have taken some critical first steps. The challenge now is to greatly expand the number of compounds tested across the panel of cell lines."
The CCLE integrates gene expression, chromosomal copy number, and massively parallel sequencing data from almost 1,000 human cancer cell lines together with pharmacological profiles for 24 anticancer drugs across roughly half of these cell lines. The scale of the project allows greater depth of genetic characterization and pharmacological annotation than previously possible with fewer cell lines. A separate effort by scientists at Massachusetts General Hospital and the Sanger Institute appears in the same issue of Nature.
To accomplish such a feat, the team of scientists relied on the genetics, computational biology, and drug-screening capabilities at the Broad, Dana-Farber, and Novartis. They chose 947 of the nearly 1,200 commercially available cancer cell lines to reflect the genomic diversity of human cancers.
"One of the strengths of the CCLE lies in the number of cell lines it surveys," said Nicolas Stransky, a computational biologist in the Cancer Program at the Broad and a co-first author of the paper. "We can focus on rare cancer subtypes and still have sufficient statistical power for analyses."
Cancer cell lines are malignant cells that have been removed from tumor tissue and cultured in the laboratory. Under controlled conditions, they can grow indefinitely. This near-immortality is an advantage for performing repeated experiments, but it can be a potential pitfall if the cells differ markedly from tumors because they lack typical surroundings. However, with relatively few exceptions, the CCLE cell lines proved to be representative genetic proxies for primary tumor subsets across multiple different cancer types.
Correlating the more than 50,000 genetic and molecular features that emerged from these cell lines created a computational challenge that the scientists met by adapting algorithms to the biological data. They tested this tool against genetic alterations known to predict sensitivity to cancer drugs, and confirmed the value of their systematic approach. Then they applied the predictive modeling methodology to genetic subtypes of cancer known to pose challenges for current treatment modalities.
For example, a variety of cancers have mutations in the NRAS gene, which activates signaling pathways important in tumor growth. Some NRAS-mutant cancers, including a subset of melanomas, may prove vulnerable to drugs that block a protein also involved in signaling, called MEK. The scope of the CCLE enabled the investigators to study approximately 40 cancer cell lines with this mutation to see if they could predict sensitivity to MEK inhibitor drugs, some of which are being studied in clinical trials.
One of the genetic features that rose to the top of their analysis was expression of the aryl hydrocarbon receptor (AHR) gene in cell lines that were highly sensitive to MEK inhibitors. This suggested that high levels of AHR may indicate higher sensitivity to MEK inhibitor drugs. Additional experiments suggested that some of these same cell lines might also depend on AHR activity, and that MEK inhibitors might simultaneously intercept AHR function in some instances.
Armed with this kind of knowledge from the CCLE, researchers may have a much clearer idea of which tumors are most likely to respond to particular drugs before using them in clinical trials, the scientists say. Patients could therefore be selected for such studies based on how likely they are to respond, given the genetic and molecular makeup of their cancers.
"Knowing that kind of information very early might help to improve the success rate of drug development, compared to a genetically 'agnostic' approach that includes any patient with advanced cancer without knowledge of a genetic profile," said Garraway.
The scientists also found new predictors of sensitivity to existing chemotherapy drugs in other cancer cell lines. Elevated levels of SLFN11 expression predicted sensitivity to topoisomerase inhibitors. Another analysis indicates that multiple myeloma may respond to IGF1 receptor inhibitors. Formal clinical studies will be required to learn if these features will hold true in patients.
"We can ask questions not only about emerging targeted therapies, but also about standard chemotherapy drugs," Garraway said. "There may be ways to identify patients who are more likely to respond to conventional chemotherapy versus those who might not. The predicted 'non-responders' may be better off trying a different regimen."
There are more volumes to be written in this encyclopedia.
"From a computational biology perspective, it's a clean, complex data set that allows many more analyses," Stransky said. "We are only scratching the surface of what can be done."
In the CCLE's next phase, analyses based on deeper sequencing, profiles of metabolic activity, and epigenetic modifications - changes in chromatin organization - will also be added.
"This is really the tip of the iceberg," Garraway said. "With these predictive modeling algorithms and with data sets of this size, their study could become an entire discipline in its own right. "
Saturday, April 21, 2012
Side effects after HPV vaccine more likely experienced by younger girls
Younger girls are more likely than adult women to report side effects after receiving Gardasil, the human papillomavirus vaccine. The side effects are non-serious and similar to those associated with other vaccines, according to a new study funded by the Centers for Disease Control and Prevention and published in the Journal of Women's Health.
As part of an ongoing study and evaluation of this relatively new vaccine, researchers surveyed 899 girls and young women (ages 11-26) within two weeks after they received the Gardasil vaccine injection in the upper arm. The survey, which took place in 2008, also found that while most girls and young women did know that the vaccine can prevent cervical cancer, and that three doses are recommended, many didn't know that the vaccine can also prevent genital warts and abnormal pap smears.
"Gardasil is an important cancer-prevention vaccine, but too few girls are getting it. Our study found that young girls do have some knowledge about the vaccine, but they need to know more. If these girls and their parents know what to expect, they will likely be less afraid of getting the vaccine," said study lead author Allison Naleway, PhD, a senior investigator with the Kaiser Permanente Center for Health Research in Portland, Ore.
Since 2006, the CDC has recommended Gardasil for girls ages 11-12, and for older girls and women (ages 13-26) who did not receive the vaccine when they were younger. The CDC also recently recommended Gardasil for boys ages 11-12, and for older boys and men (ages 13-21) who did not receive the vaccine when they were younger.
Information about side effects has been reported by the manufacturer, the CDC, and by the federal government's Vaccine Adverse Event Reporting System, but this study is one of the first to survey girls themselves shortly after they received the vaccine. Many other studies have relied on information reported by health care providers and parents.
For this study, researchers used electronic health records to identify 3,490 Oregon and Washington girls and young women (ages 11-26) who received their first dose of HPV vaccine between February and September of 2008. Within a week of vaccination, researchers sent out surveys to young women ages 18-26. For girls under 18, researchers notified parents that their daughters would be receiving the surveys the following week, and gave the parents a choice to opt out. The survey included 50 questions about vaccine side effects, the girls' knowledge of the vaccine and the HPV virus, and about what kind of information their doctors shared with them before vaccine administration.
Of the 899 girls and women who responded to the survey, 78 percent reported pain when receiving the vaccine. Seventeen percent reported bruising or discoloration, 14 percent said they had swelling at the injection site, 15 percent reported dizziness, and 1 percent of the girls reported fainting.
Younger girls were more likely to have received other vaccines such as tetanus, meningitis and hepatitis A at the same time they received the HPV vaccine, and they were also more likely to report side effects. For example, 84 percent of girls aged 11-12 reported pain with the injection vs. 74 percent of women aged 18-26. Nineteen percent of girls aged 11-12 reported feeling dizzy after receiving the vaccine, but fewer than half that many (8 percent) of women aged 18-26 reported dizziness.
"These side effects are non-serious and very manageable," said Mike Wilmington, MD, a Kaiser Permanente pediatrician in Vancouver, Wash., who was not involved in the study. "The main complaint I hear about is pain with the injection, but there are ways to lessen the pain. Some girls will feel dizzy after this and other vaccines, so I follow CDC guidelines and have them sit or lie down for a few minutes after receiving the vaccine."
Eighty-four percent of girls and young women said they knew that the HPV virus can cause cervical cancer, but only half reported knowing that it can also cause genital warts and abnormal pap smears. Most respondents said their providers told them they needed three doses of the vaccine, and most also said their providers talked with them about the vaccine's benefits, possible side effects, and about HPV infection. Most girls, however, said their providers did not discuss genital warts or abnormal pap smears, and only one-fifth of girls said their provider asked them to sit and rest after receiving the vaccination.
As part of an ongoing study and evaluation of this relatively new vaccine, researchers surveyed 899 girls and young women (ages 11-26) within two weeks after they received the Gardasil vaccine injection in the upper arm. The survey, which took place in 2008, also found that while most girls and young women did know that the vaccine can prevent cervical cancer, and that three doses are recommended, many didn't know that the vaccine can also prevent genital warts and abnormal pap smears.
"Gardasil is an important cancer-prevention vaccine, but too few girls are getting it. Our study found that young girls do have some knowledge about the vaccine, but they need to know more. If these girls and their parents know what to expect, they will likely be less afraid of getting the vaccine," said study lead author Allison Naleway, PhD, a senior investigator with the Kaiser Permanente Center for Health Research in Portland, Ore.
Since 2006, the CDC has recommended Gardasil for girls ages 11-12, and for older girls and women (ages 13-26) who did not receive the vaccine when they were younger. The CDC also recently recommended Gardasil for boys ages 11-12, and for older boys and men (ages 13-21) who did not receive the vaccine when they were younger.
Information about side effects has been reported by the manufacturer, the CDC, and by the federal government's Vaccine Adverse Event Reporting System, but this study is one of the first to survey girls themselves shortly after they received the vaccine. Many other studies have relied on information reported by health care providers and parents.
For this study, researchers used electronic health records to identify 3,490 Oregon and Washington girls and young women (ages 11-26) who received their first dose of HPV vaccine between February and September of 2008. Within a week of vaccination, researchers sent out surveys to young women ages 18-26. For girls under 18, researchers notified parents that their daughters would be receiving the surveys the following week, and gave the parents a choice to opt out. The survey included 50 questions about vaccine side effects, the girls' knowledge of the vaccine and the HPV virus, and about what kind of information their doctors shared with them before vaccine administration.
Of the 899 girls and women who responded to the survey, 78 percent reported pain when receiving the vaccine. Seventeen percent reported bruising or discoloration, 14 percent said they had swelling at the injection site, 15 percent reported dizziness, and 1 percent of the girls reported fainting.
Younger girls were more likely to have received other vaccines such as tetanus, meningitis and hepatitis A at the same time they received the HPV vaccine, and they were also more likely to report side effects. For example, 84 percent of girls aged 11-12 reported pain with the injection vs. 74 percent of women aged 18-26. Nineteen percent of girls aged 11-12 reported feeling dizzy after receiving the vaccine, but fewer than half that many (8 percent) of women aged 18-26 reported dizziness.
"These side effects are non-serious and very manageable," said Mike Wilmington, MD, a Kaiser Permanente pediatrician in Vancouver, Wash., who was not involved in the study. "The main complaint I hear about is pain with the injection, but there are ways to lessen the pain. Some girls will feel dizzy after this and other vaccines, so I follow CDC guidelines and have them sit or lie down for a few minutes after receiving the vaccine."
Eighty-four percent of girls and young women said they knew that the HPV virus can cause cervical cancer, but only half reported knowing that it can also cause genital warts and abnormal pap smears. Most respondents said their providers told them they needed three doses of the vaccine, and most also said their providers talked with them about the vaccine's benefits, possible side effects, and about HPV infection. Most girls, however, said their providers did not discuss genital warts or abnormal pap smears, and only one-fifth of girls said their provider asked them to sit and rest after receiving the vaccination.
Friday, April 20, 2012
Dramatic rise in skin cancer
Even as the rates of some cancers are falling, Mayo Clinic is seeing an alarming trend: the dramatic rise of skin cancer, especially among people under 40. According to a study by Mayo Clinic researchers published in the April issue of Mayo Clinic Proceedings, the incidence of melanoma has escalated, and young women are the hardest hit.
"We anticipated we'd find rising rates, as other studies are suggesting, but we found an even higher incidence than the National Cancer Institute had reported using the Surveillance, Epidemiology and End Result database, and in particular, a dramatic rise in women in their 20s and 30s," says lead investigator Jerry Brewer, M.D., a Mayo Clinic dermatologist. Researchers conducted a population-based study using records from the Rochester Epidemiology Project, a decades-long database of all patient care in Olmsted County, Minn. They looked for first-time diagnoses of melanoma in patients 18 to 39 from 1970 to 2009. The study found the incidence of melanoma increased eightfold among young women and fourfold among young men. The lifetime risk of melanoma is higher in males than females, but the opposite is true in young adults and adolescents, Dr. Brewer says.
Researchers also found mortality rates from the disease have improved over the years, likely due to early detection of skin cancer and prompt medical care.
"People are now more aware of their skin and of the need to see a doctor when they see changes," Dr. Brewer says. "As a result, many cases may be caught before the cancer advances to a deep melanoma, which is harder to treat."
The researchers speculate that the use of indoor tanning beds is a key culprit in the rising cancer rate in young women.
"A recent study reported that people who use indoor tanning beds frequently are 74 percent more likely to develop melanoma, and we know young women are more likely to use them than young men," Dr. Brewer says. Despite abundant information about the dangers of tanning beds, he adds, young women continue to use them. "The results of this study emphasize the importance of active interventions to decrease risk factors for skin cancer and, in particular, to continue to alert young women that indoor tanning has carcinogenic effects that increase the risk of melanoma."
Janey Helland, of Mapleton, Minn., didn't think twice when tanning in high school and college.
"I used tanning beds to get ready for homecoming and prom," she says. "In college, I tanned before a trip to Barbados because I didn't want to get sunburned." At age 21, Helland noticed an abnormal spot on her leg. It was melanoma, and the diagnosis changed Helland's life. "I really didn't know what my future was going to look like, or if I'd even have one."
Two years later, she is cancer-free and dedicated to educating others. "I would advocate that it's better to be safe than sorry," she says. "My advice is to educate yourself and research the risk factors."
Childhood sunburns and ultraviolet exposure in adulthood may also contribute to melanoma development, the researchers say.
"We anticipated we'd find rising rates, as other studies are suggesting, but we found an even higher incidence than the National Cancer Institute had reported using the Surveillance, Epidemiology and End Result database, and in particular, a dramatic rise in women in their 20s and 30s," says lead investigator Jerry Brewer, M.D., a Mayo Clinic dermatologist. Researchers conducted a population-based study using records from the Rochester Epidemiology Project, a decades-long database of all patient care in Olmsted County, Minn. They looked for first-time diagnoses of melanoma in patients 18 to 39 from 1970 to 2009. The study found the incidence of melanoma increased eightfold among young women and fourfold among young men. The lifetime risk of melanoma is higher in males than females, but the opposite is true in young adults and adolescents, Dr. Brewer says.
Researchers also found mortality rates from the disease have improved over the years, likely due to early detection of skin cancer and prompt medical care.
"People are now more aware of their skin and of the need to see a doctor when they see changes," Dr. Brewer says. "As a result, many cases may be caught before the cancer advances to a deep melanoma, which is harder to treat."
The researchers speculate that the use of indoor tanning beds is a key culprit in the rising cancer rate in young women.
"A recent study reported that people who use indoor tanning beds frequently are 74 percent more likely to develop melanoma, and we know young women are more likely to use them than young men," Dr. Brewer says. Despite abundant information about the dangers of tanning beds, he adds, young women continue to use them. "The results of this study emphasize the importance of active interventions to decrease risk factors for skin cancer and, in particular, to continue to alert young women that indoor tanning has carcinogenic effects that increase the risk of melanoma."
Janey Helland, of Mapleton, Minn., didn't think twice when tanning in high school and college.
"I used tanning beds to get ready for homecoming and prom," she says. "In college, I tanned before a trip to Barbados because I didn't want to get sunburned." At age 21, Helland noticed an abnormal spot on her leg. It was melanoma, and the diagnosis changed Helland's life. "I really didn't know what my future was going to look like, or if I'd even have one."
Two years later, she is cancer-free and dedicated to educating others. "I would advocate that it's better to be safe than sorry," she says. "My advice is to educate yourself and research the risk factors."
Childhood sunburns and ultraviolet exposure in adulthood may also contribute to melanoma development, the researchers say.
Thursday, April 19, 2012
Cancerous cells in mice treated using nanoparticles and magnatic current
Using nanoparticles and alternating magnetic fields, University of Georgia scientists have found that head and neck cancerous tumor cells in mice can be killed in half an hour without harming healthy cells.
The findings, published recently in the journal Theranostics, mark the first time to the researchers' knowledge this cancer type has been treated using magnetic iron oxide nanoparticle-induced hyperthermia, or above-normal body temperatures, in laboratory mice.
"We show that we can use a small concentration of nanoparticles to kill the cancer cells," said Qun Zhao, lead author and assistant professor of physics in the Franklin College of Arts and Sciences. Researchers found that the treatment easily destroyed the cells of cancerous tumors that were composed entirely of a type of tissue that covers the surface of a body, which is also known as epithelium.
Several researchers around the globe are exploring the use of heated nanoparticles as a potential cancer treatment. Previous studies also have shown that high temperatures created by combining magnetic iron oxide nanoparticles with strong alternating magnetic currents can create enough heat to kill tumor cells. Zhao said he is optimistic about his findings, but explained that future studies will need to include larger animals before a human clinical trial could be considered.
For the experiment, researchers injected a tiny amount -- a tenth of a teaspoon, or 0.5 milliliter -- of nanoparticle solution directly into the tumor site. With the mouse relaxed under anesthesia, they placed the animal in a plastic tube wrapped with a wire coil that generated magnetic fields that alternated directions 100,000 times each second. The magnetic fields produced by the wire coil heated only the concentrated nanoparticles within the cancerous tumor and left the surrounding healthy cells and tissue unharmed.
Zhao said the study paves the way for additional research that might investigate how to use a biodegradable nanoparticle material similar to magnetic iron oxide for other roles in fighting cancer, such as carrying and delivering anti-cancer drugs to the tumor site.
"When the cancer cell is experiencing this heated environment, then it becomes more susceptible to drugs," Zhao said.
Magnetic iron oxide nanoparticles could be useful in improving the contrast in magnetic resonance imaging at a cancer site, he said. In other words, the nanoparticles could help physicians detect cancer even if the cancer is not visible to the naked eye with an MRI scan.
"The reason I am interested in using these magnetic nanoparticles is because we hope to one day be able to offer diagnosis and therapeutics, or theranostics, using a single agent," Zhao said.
The findings, published recently in the journal Theranostics, mark the first time to the researchers' knowledge this cancer type has been treated using magnetic iron oxide nanoparticle-induced hyperthermia, or above-normal body temperatures, in laboratory mice.
"We show that we can use a small concentration of nanoparticles to kill the cancer cells," said Qun Zhao, lead author and assistant professor of physics in the Franklin College of Arts and Sciences. Researchers found that the treatment easily destroyed the cells of cancerous tumors that were composed entirely of a type of tissue that covers the surface of a body, which is also known as epithelium.
Several researchers around the globe are exploring the use of heated nanoparticles as a potential cancer treatment. Previous studies also have shown that high temperatures created by combining magnetic iron oxide nanoparticles with strong alternating magnetic currents can create enough heat to kill tumor cells. Zhao said he is optimistic about his findings, but explained that future studies will need to include larger animals before a human clinical trial could be considered.
For the experiment, researchers injected a tiny amount -- a tenth of a teaspoon, or 0.5 milliliter -- of nanoparticle solution directly into the tumor site. With the mouse relaxed under anesthesia, they placed the animal in a plastic tube wrapped with a wire coil that generated magnetic fields that alternated directions 100,000 times each second. The magnetic fields produced by the wire coil heated only the concentrated nanoparticles within the cancerous tumor and left the surrounding healthy cells and tissue unharmed.
Zhao said the study paves the way for additional research that might investigate how to use a biodegradable nanoparticle material similar to magnetic iron oxide for other roles in fighting cancer, such as carrying and delivering anti-cancer drugs to the tumor site.
"When the cancer cell is experiencing this heated environment, then it becomes more susceptible to drugs," Zhao said.
Magnetic iron oxide nanoparticles could be useful in improving the contrast in magnetic resonance imaging at a cancer site, he said. In other words, the nanoparticles could help physicians detect cancer even if the cancer is not visible to the naked eye with an MRI scan.
"The reason I am interested in using these magnetic nanoparticles is because we hope to one day be able to offer diagnosis and therapeutics, or theranostics, using a single agent," Zhao said.
Wednesday, April 18, 2012
Embryonic stem cells shift metabolism in cancer-like way upon implanting in uterus
Shortly after a mouse embryo starts to form, some of its stem cells undergo a dramatic metabolic shift to enter the next stage of development, Seattle researchers have reported. These stem cells start using and producing energy like cancer cells.
"These findings not only have implications for stem cell research and the study of how embryos grow and take shape, but also for cancer therapy," said the senior author of the study, Dr. Hannele Ruohola-Baker, University of Washington professor of biochemistry. The study was collaborative among several research labs in Seattle.
The metabolic transition they discovered occurs very early as the mouse embryo, barely more than a speck of dividing cells, implants in the mother's uterus. The change is driven by low oxygen conditions, Ruohola-Baker explained.
The researchers also saw a specific type of biochemical slowdown in the stem cells' mitochondria -- the cells' powerhouses. The phenomenon previously was associated with aging and disease. This was the first example of the same downshift controlling normal early embryonic development.
"This downshift coincides with the time when the germ line, the keeper of the genome for the next generation, is set aside," Ruohola-Baker said.. "Hence reduction of mitochondrial reactive oxygen species may be nature's way to protect the future."
Embryonic stem cells are called pluripotent because they have the ability to renew themselves and have the potential to become any cell in the body. Self-sustaining and versatile are qualities necessary for the growth, repair and maintenance of the body -- and for regenerative medicine therapies.
Although they share these sought-after qualities, "Pluripotent stem cells come in several flavors," Ruohola-Baker explained. They differ in subtle ways that expand or shrink their capacities as the raw living material from which animals are shaped.
There's a big reason why the researchers wanted to understand the distinction between the stem cells that make up the inner cell mass of the free-floating mouse embryo, and those in the epiblast, or implantation stage. Mouse embryonic cells at the epiblast stage more closely resemble human embryonic stem cells -- and cancer cells.
Human stem cells and mouse epiblast stem cells have lower mitochondrial respiration activity than do earlier stage mouse stem cells. This reduction occurs despite the fact that the later stage stem cells have more mature mitochondria. The researchers confirmed that certain genes that control mitochondria are turned down during the transition from inner cells mass to epiblast cells.
Instead, the transitioning cells obtain their energy exclusively from breaking down a sugar, glucose. In contrast, the earlier stage mouse embryonic stem cells have more energy options, dynamically switching from mitochondrial respiration to glucose breakdown on demand.
As the embryo enlarges from a few dividing cells to a dense mass that buries into uterus for further development, oxygen comes at a premium.
The researchers discovered that the low-oxygen conditions activate a transcription factor called hypoxia-inducible factor 1alpha. This factor is sufficient to drive mouse embryonic stem cells to rely exclusively on glucose metabolism for their energy. The next challenge is to reveal whether the metabolic switch is deterministic for the fate of these stem cells, in normal as well as in cancer development.
This forced metabolic switch may determine the functional fate of some of the tiny mass of cells making up the primordial embryo. They transition first into epiblast stem cells and, afterward produce the entire developing embryo.
In cancer cells, the shift to a sugar-busting metabolism is known as the Warburg effect, the researchers explain. The Warburg effect sets in motion the biochemical activities that provide the fuel and materials required for rapid tumor cell growth and division.
The Warburg effect in embryonic cells, the researcher proposed, "may serve a similar function in preparation for the dramatic burst of embryonic growth and for the formation of the layers of the early embryo that later will become organs and other body structures."
"These findings not only have implications for stem cell research and the study of how embryos grow and take shape, but also for cancer therapy," said the senior author of the study, Dr. Hannele Ruohola-Baker, University of Washington professor of biochemistry. The study was collaborative among several research labs in Seattle.
The metabolic transition they discovered occurs very early as the mouse embryo, barely more than a speck of dividing cells, implants in the mother's uterus. The change is driven by low oxygen conditions, Ruohola-Baker explained.
The researchers also saw a specific type of biochemical slowdown in the stem cells' mitochondria -- the cells' powerhouses. The phenomenon previously was associated with aging and disease. This was the first example of the same downshift controlling normal early embryonic development.
"This downshift coincides with the time when the germ line, the keeper of the genome for the next generation, is set aside," Ruohola-Baker said.. "Hence reduction of mitochondrial reactive oxygen species may be nature's way to protect the future."
Embryonic stem cells are called pluripotent because they have the ability to renew themselves and have the potential to become any cell in the body. Self-sustaining and versatile are qualities necessary for the growth, repair and maintenance of the body -- and for regenerative medicine therapies.
Although they share these sought-after qualities, "Pluripotent stem cells come in several flavors," Ruohola-Baker explained. They differ in subtle ways that expand or shrink their capacities as the raw living material from which animals are shaped.
There's a big reason why the researchers wanted to understand the distinction between the stem cells that make up the inner cell mass of the free-floating mouse embryo, and those in the epiblast, or implantation stage. Mouse embryonic cells at the epiblast stage more closely resemble human embryonic stem cells -- and cancer cells.
Human stem cells and mouse epiblast stem cells have lower mitochondrial respiration activity than do earlier stage mouse stem cells. This reduction occurs despite the fact that the later stage stem cells have more mature mitochondria. The researchers confirmed that certain genes that control mitochondria are turned down during the transition from inner cells mass to epiblast cells.
Instead, the transitioning cells obtain their energy exclusively from breaking down a sugar, glucose. In contrast, the earlier stage mouse embryonic stem cells have more energy options, dynamically switching from mitochondrial respiration to glucose breakdown on demand.
As the embryo enlarges from a few dividing cells to a dense mass that buries into uterus for further development, oxygen comes at a premium.
The researchers discovered that the low-oxygen conditions activate a transcription factor called hypoxia-inducible factor 1alpha. This factor is sufficient to drive mouse embryonic stem cells to rely exclusively on glucose metabolism for their energy. The next challenge is to reveal whether the metabolic switch is deterministic for the fate of these stem cells, in normal as well as in cancer development.
This forced metabolic switch may determine the functional fate of some of the tiny mass of cells making up the primordial embryo. They transition first into epiblast stem cells and, afterward produce the entire developing embryo.
In cancer cells, the shift to a sugar-busting metabolism is known as the Warburg effect, the researchers explain. The Warburg effect sets in motion the biochemical activities that provide the fuel and materials required for rapid tumor cell growth and division.
The Warburg effect in embryonic cells, the researcher proposed, "may serve a similar function in preparation for the dramatic burst of embryonic growth and for the formation of the layers of the early embryo that later will become organs and other body structures."
Identifying specific cancers using molecular analysis
Researchers from Huntsman Cancer Institute (HCI) at the University of Utah report they have discovered a method to identify cancer-causing rearrangements of genetic material called chromosomal translocations quickly, accurately, and inexpensively. A description of the method and the research results appear online in this month's issue of the EMBO Molecular Medicine journal.
Many cancers result from chromosomal translocations in tumor cells. Hundreds of cancer-causing translocations have been discovered, but current methods for detecting them have significant shortcomings.
The technique, developed in the lab of Stephen Lessnick, M.D., Ph.D., director of the Center for Children's Cancer Research at HCI, combines microarray technology, which can look for thousands of translocations in a single test, with a novel antibody that is used to detect the presence of the translocation . "We're moving past the age when a pathologist looking through the microscope at a tumor sample is the best way to diagnose what type of cancer it is," said Lessnick. "The molecular tests currently available are slow, inefficient, and expensive, and one of the biggest issues is that you need high-quality tumor samples, not always available in the clinical setting, to do them." According to Lessnick, his method tolerates real-life specimens much better than the current standard techniques.
"Originally, this method was used in HCI's Cairns lab (headed by Bradley R. Cairns, Ph.D.) to study RNA in yeast. We took their method and applied it to our study of chromosomal translocations in human tissue," Lessnick said. He said the next task is to find a commercial partner to develop this research from a 'proof of principle' into a diagnostic test that doctors can use to help their patients.
"With this method, there's potential to develop a single array that could test for every known cancer-causing translocation simultaneously. Currently, a clinician has to decide beforehand which specific cancer to test," he said.
The research used Ewing's sarcoma (a rare childhood cancer) as the case study for developing the method, but Lessnick maintains that the technology can be easily applied to any type of cancer caused by a translocation.
Many cancers result from chromosomal translocations in tumor cells. Hundreds of cancer-causing translocations have been discovered, but current methods for detecting them have significant shortcomings.
The technique, developed in the lab of Stephen Lessnick, M.D., Ph.D., director of the Center for Children's Cancer Research at HCI, combines microarray technology, which can look for thousands of translocations in a single test, with a novel antibody that is used to detect the presence of the translocation . "We're moving past the age when a pathologist looking through the microscope at a tumor sample is the best way to diagnose what type of cancer it is," said Lessnick. "The molecular tests currently available are slow, inefficient, and expensive, and one of the biggest issues is that you need high-quality tumor samples, not always available in the clinical setting, to do them." According to Lessnick, his method tolerates real-life specimens much better than the current standard techniques.
"Originally, this method was used in HCI's Cairns lab (headed by Bradley R. Cairns, Ph.D.) to study RNA in yeast. We took their method and applied it to our study of chromosomal translocations in human tissue," Lessnick said. He said the next task is to find a commercial partner to develop this research from a 'proof of principle' into a diagnostic test that doctors can use to help their patients.
"With this method, there's potential to develop a single array that could test for every known cancer-causing translocation simultaneously. Currently, a clinician has to decide beforehand which specific cancer to test," he said.
The research used Ewing's sarcoma (a rare childhood cancer) as the case study for developing the method, but Lessnick maintains that the technology can be easily applied to any type of cancer caused by a translocation.
Tuesday, April 17, 2012
Experts say that more than half of all cancer disease is preventable
More than half of all cancer is preventable, and society has the knowledge to act on this information today, according to Washington University public health researchers at the Siteman Cancer Center in St. Louis.
In a review article published in Science Translational Medicine March 28, the investigators outline obstacles they say stand in the way of making a huge dent in the cancer burden in the United States and around the world.
"We actually have an enormous amount of data about the causes and preventability of cancer," says epidemiologist Graham A. Colditz, MD, DrPH, the Niess-Gain Professor at the School of Medicine and associate director of prevention and control at the Siteman Cancer Center. "It's time we made an investment in implementing what we know."
What we know, according to Colditz and his co-authors, is that lifestyle choices people make and that society can influence in a number of ways -- from tobacco use to diet and exercise -- play a significant role in causing cancer. Specifically, the researchers cite data demonstrating that smoking alone is responsible for a third of all cancer cases in the United States. Excess body weight and obesity account for another 20 percent.
But beyond individual habits, they argue that the structure of society itself -- from medical research funding to building design and food subsidies -- influences the extent of the cancer burden and can be changed to reduce it.
The obstacles they see to implementing broad cancer prevention strategies are:
Skepticism that cancer can be prevented. Smoking rates in different states demonstrate that 75 percent of lung cancer in the United States could be prevented with elimination of cigarette smoking.
The short-term focus of cancer research. Benefits of prevention may be underestimated because they take decades to show up, and research funding often spans five years or less.
Intervening too late in life to prevent cancer. Strategies like vaccination against cancer-causing viruses, such as the human papilloma virus that causes cervical cancer, work best when begun early, in this case before young people begin sexual activity.
Research focuses on treatment, not prevention. Treatments focus only on a single organ after diagnosis but behavioral changes reduce cancer and death rates from many chronic diseases.
Debate among scientists. They say health experts have a moral responsibility to highlight cancer risk factors even without knowing the biological mechanism by which they cause cancer.
Societal factors that affect health. Tobacco policy and government subsidies don't do enough to discourage unhealthy behavior, and in some cases they make the unhealthy options more accessible, especially in low-income communities.
Lack of collaboration across disciplines. Scientists and health experts must work together to learn what causes cancer, communicate that to the public and work with community leaders to implement policies that help people lead healthier lives, they say.
The complexity of implementing broad changes. With so many players involved, from health-care providers to government regulators to individuals, it will be difficult to implement broad change over the long term.
According to the American Cancer Society, an estimated 1,638,910 new cancer cases will be diagnosed this year in the United States. Also this year, 577,190 Americans are expected to die of cancer. Only heart disease kills more people in this country. And Colditz's research has shown that these cancer prevention strategies would reduce the burden of heart disease and other chronic conditions as well.
Despite the obstacles, Colditz and his colleagues point to some successes that they say demonstrate that broad change is possible. One example is the relatively quick elimination of unhealthy trans fats from the national diet. And the National Cancer Institute (NCI) has reported that lung cancer rates are declining in both men and women, supporting the benefits of tighter tobacco control policy.
"After working in public health for 25 years, I've learned that if we want to change health, we need to change policy," says co-author Sarah J. Gehlert, PhD, the E. Desmond Lee Professor of Racial and Ethnic Diversity at the Brown School of Social Work and the School of Medicine. "Stricter tobacco policy is a good example. But we can't make policy change on our own. We can tell the story, but it requires a critical mass of people to talk more forcefully about the need for change."
In a review article published in Science Translational Medicine March 28, the investigators outline obstacles they say stand in the way of making a huge dent in the cancer burden in the United States and around the world.
"We actually have an enormous amount of data about the causes and preventability of cancer," says epidemiologist Graham A. Colditz, MD, DrPH, the Niess-Gain Professor at the School of Medicine and associate director of prevention and control at the Siteman Cancer Center. "It's time we made an investment in implementing what we know."
What we know, according to Colditz and his co-authors, is that lifestyle choices people make and that society can influence in a number of ways -- from tobacco use to diet and exercise -- play a significant role in causing cancer. Specifically, the researchers cite data demonstrating that smoking alone is responsible for a third of all cancer cases in the United States. Excess body weight and obesity account for another 20 percent.
But beyond individual habits, they argue that the structure of society itself -- from medical research funding to building design and food subsidies -- influences the extent of the cancer burden and can be changed to reduce it.
The obstacles they see to implementing broad cancer prevention strategies are:
Skepticism that cancer can be prevented. Smoking rates in different states demonstrate that 75 percent of lung cancer in the United States could be prevented with elimination of cigarette smoking.
The short-term focus of cancer research. Benefits of prevention may be underestimated because they take decades to show up, and research funding often spans five years or less.
Intervening too late in life to prevent cancer. Strategies like vaccination against cancer-causing viruses, such as the human papilloma virus that causes cervical cancer, work best when begun early, in this case before young people begin sexual activity.
Research focuses on treatment, not prevention. Treatments focus only on a single organ after diagnosis but behavioral changes reduce cancer and death rates from many chronic diseases.
Debate among scientists. They say health experts have a moral responsibility to highlight cancer risk factors even without knowing the biological mechanism by which they cause cancer.
Societal factors that affect health. Tobacco policy and government subsidies don't do enough to discourage unhealthy behavior, and in some cases they make the unhealthy options more accessible, especially in low-income communities.
Lack of collaboration across disciplines. Scientists and health experts must work together to learn what causes cancer, communicate that to the public and work with community leaders to implement policies that help people lead healthier lives, they say.
The complexity of implementing broad changes. With so many players involved, from health-care providers to government regulators to individuals, it will be difficult to implement broad change over the long term.
According to the American Cancer Society, an estimated 1,638,910 new cancer cases will be diagnosed this year in the United States. Also this year, 577,190 Americans are expected to die of cancer. Only heart disease kills more people in this country. And Colditz's research has shown that these cancer prevention strategies would reduce the burden of heart disease and other chronic conditions as well.
Despite the obstacles, Colditz and his colleagues point to some successes that they say demonstrate that broad change is possible. One example is the relatively quick elimination of unhealthy trans fats from the national diet. And the National Cancer Institute (NCI) has reported that lung cancer rates are declining in both men and women, supporting the benefits of tighter tobacco control policy.
"After working in public health for 25 years, I've learned that if we want to change health, we need to change policy," says co-author Sarah J. Gehlert, PhD, the E. Desmond Lee Professor of Racial and Ethnic Diversity at the Brown School of Social Work and the School of Medicine. "Stricter tobacco policy is a good example. But we can't make policy change on our own. We can tell the story, but it requires a critical mass of people to talk more forcefully about the need for change."
Monday, April 16, 2012
To combat skin cancer researchers are building melanoma vaccine
Mayo Clinic researchers have trained mouse immune systems to eradicate skin cancer from within, using a genetic combination of human DNA from melanoma cells and a cousin of the rabies virus. The strategy, called cancer immunotherapy, uses a genetically engineered version of the vesicular stomatitis virus to deliver a broad spectrum of genes derived from melanoma cancer cells directly into tumors. In early studies, 60 percent of tumor-burdened mice were cured in fewer than three months and with minimal side effects.
"We believe that this new technique will help us to identify a whole new set of genes that encode antigens that are important in stimulating the immune system to reject cancer. In particular, we have seen that several proteins need to be expressed together to generate the most effective rejection of the tumors in mice," says Richard Vile, Ph.D., a Mayo Clinic researcher in the Department of Molecular Medicine and a coauthor of the study, along with Jose Pulido, M.D., a Mayo Clinic ophthalmologist and ocular oncologist.
Dr. Vile's success with melanoma adds to Mayo Clinic's growing portfolio of experimental cancer vaccines, which includes an active clinical trial of vesicular stomatitis vaccines for liver cancers. Future studies could include similar vaccines for more aggressive cancers, such as lung, brain and pancreatic.
"I do believe we can create vaccines that will knock them off one by one," Dr. Vile says. "By vaccinating against multiple proteins at once, we hope that we will be able to treat both the primary tumor and also protect against recurrence."
The immune system functions on a seek-and-destroy platform and has fine-tuned its capacity to identify viral invaders such as vesicular stomatitis virus. Part of the appeal of building cancer vaccines from the whole spectrum of tumor DNA is that tumors can adapt to the repeated attacks of a healthy immune system and display fewer antigens (or signposts) that the immune system can identify.
Cancers can learn to hide from a normal immune system, but appear unable to escape an immune system trained by the vesicular stomatitis virus with the wide range of DNA used in the library approach.
"Nobody knows how many antigens the immune system can really see on tumor cells," says Dr. Vile. "By expressing all of these proteins in highly immunogenic viruses, we increased their visibility to the immune system. The immune system now thinks it is being invaded by the viruses, which are expressing cancer-related antigens that should be eliminated."
Much immunotherapy research has slowed because of researchers' inability to isolate a sufficiently diverse collection of antigens in tumor cells. Tumors in these scenarios are able to mutate and reestablish themselves in spite of the body's immune system.
"We believe that this new technique will help us to identify a whole new set of genes that encode antigens that are important in stimulating the immune system to reject cancer. In particular, we have seen that several proteins need to be expressed together to generate the most effective rejection of the tumors in mice," says Richard Vile, Ph.D., a Mayo Clinic researcher in the Department of Molecular Medicine and a coauthor of the study, along with Jose Pulido, M.D., a Mayo Clinic ophthalmologist and ocular oncologist.
Dr. Vile's success with melanoma adds to Mayo Clinic's growing portfolio of experimental cancer vaccines, which includes an active clinical trial of vesicular stomatitis vaccines for liver cancers. Future studies could include similar vaccines for more aggressive cancers, such as lung, brain and pancreatic.
"I do believe we can create vaccines that will knock them off one by one," Dr. Vile says. "By vaccinating against multiple proteins at once, we hope that we will be able to treat both the primary tumor and also protect against recurrence."
The immune system functions on a seek-and-destroy platform and has fine-tuned its capacity to identify viral invaders such as vesicular stomatitis virus. Part of the appeal of building cancer vaccines from the whole spectrum of tumor DNA is that tumors can adapt to the repeated attacks of a healthy immune system and display fewer antigens (or signposts) that the immune system can identify.
Cancers can learn to hide from a normal immune system, but appear unable to escape an immune system trained by the vesicular stomatitis virus with the wide range of DNA used in the library approach.
"Nobody knows how many antigens the immune system can really see on tumor cells," says Dr. Vile. "By expressing all of these proteins in highly immunogenic viruses, we increased their visibility to the immune system. The immune system now thinks it is being invaded by the viruses, which are expressing cancer-related antigens that should be eliminated."
Much immunotherapy research has slowed because of researchers' inability to isolate a sufficiently diverse collection of antigens in tumor cells. Tumors in these scenarios are able to mutate and reestablish themselves in spite of the body's immune system.
Sunday, April 15, 2012
Link between inflammation and breast cancer metastases identified
The incidence of breast cancer-associated metastasis was increased in animal models of the chronic inflammatory condition arthritis, according to results of a preclinical study presented at the AACR Annual Meeting 2012, held in Chicago March 31 -- April 4. The results indicate that inflammatory cells known as mast cells play a key role in this increase and that interfering with mast cells reduces the occurrence of bone and lung metastases.
"The most devastating aspect of breast cancer is the emergence of tumor cells that grow to distant organs," said Lopamudra Das Roy, Ph.D., research assistant professor at the University of North Carolina in Charlotte, N.C. "It has been reported that sites of chronic inflammation are associated with the establishment and growth of tumor cells."
Prior research conducted by Das Roy established that the incidence of breast cancer metastasis to the bone and lungs was increased in arthritic mice. Because both breast cancer and arthritis are prevalent in women, specifically postmenopausal women, the researchers conducted an additional study using two groups of mice to identify what might be causing the association between arthritis and breast cancer metastases.
The first group of mice had spontaneous arthritis and was induced to have breast cancer. The second group of mice had spontaneous breast cancer and was induced to have arthritis. Because mice in both groups had enhanced numbers of mast cells within the bone and lung, Das Roy and colleagues focused on understanding how these cells might influence breast cancer metastasis.
"We found that there were many proinflammatory factors that are upregulated in the arthritic microenvironment and several of these proinflammatory factors known to influence metastases are produced by mast cells, which are activated by tumor-derived stem cell factor (SCF) binding to its receptor c-Kit," Das Roy said.
A subsequent key finding was that SCF/c-Kit signaling was increased in arthritic mice with breast cancer versus nonarthritic mice with breast cancer. This set the stage for examining the effects of blocking this signaling.
When the mice were treated with a therapy to target the c-Kit mast cell receptor in combination with celecoxib (a drug used to treat autoimmune arthritis), the incidence of breast cancer metastasis to the bone and lung was greatly reduced.
"The clinical implications of this research are huge," Das Roy said. "We already have data that show that women with breast cancer and arthritis have lower survival as compared with women with breast cancer and no arthritis. This research indicates that we may be able to design a therapy to block SCF/c-Kit signaling, which could help reduce metastases to the bone and lungs."
"The most devastating aspect of breast cancer is the emergence of tumor cells that grow to distant organs," said Lopamudra Das Roy, Ph.D., research assistant professor at the University of North Carolina in Charlotte, N.C. "It has been reported that sites of chronic inflammation are associated with the establishment and growth of tumor cells."
Prior research conducted by Das Roy established that the incidence of breast cancer metastasis to the bone and lungs was increased in arthritic mice. Because both breast cancer and arthritis are prevalent in women, specifically postmenopausal women, the researchers conducted an additional study using two groups of mice to identify what might be causing the association between arthritis and breast cancer metastases.
The first group of mice had spontaneous arthritis and was induced to have breast cancer. The second group of mice had spontaneous breast cancer and was induced to have arthritis. Because mice in both groups had enhanced numbers of mast cells within the bone and lung, Das Roy and colleagues focused on understanding how these cells might influence breast cancer metastasis.
"We found that there were many proinflammatory factors that are upregulated in the arthritic microenvironment and several of these proinflammatory factors known to influence metastases are produced by mast cells, which are activated by tumor-derived stem cell factor (SCF) binding to its receptor c-Kit," Das Roy said.
A subsequent key finding was that SCF/c-Kit signaling was increased in arthritic mice with breast cancer versus nonarthritic mice with breast cancer. This set the stage for examining the effects of blocking this signaling.
When the mice were treated with a therapy to target the c-Kit mast cell receptor in combination with celecoxib (a drug used to treat autoimmune arthritis), the incidence of breast cancer metastasis to the bone and lung was greatly reduced.
"The clinical implications of this research are huge," Das Roy said. "We already have data that show that women with breast cancer and arthritis have lower survival as compared with women with breast cancer and no arthritis. This research indicates that we may be able to design a therapy to block SCF/c-Kit signaling, which could help reduce metastases to the bone and lungs."
US cancer death rates continue to decline
A report from the nation's leading cancer organizations shows rates of death in the United States from all cancers for men and women continued to decline between 2004 and 2008. The findings come from the latest Annual Report to the Nation on the Status of Cancer.
The report also finds that the overall rate of new cancer diagnoses for men and women combined decreased an average of less than one percent per year from 1998 through 2006, with rates leveling off from 2006 through 2008. Edward J. Benz, Jr., MD, president of Dana-Farber Cancer Institute in Boston, called the news encouraging, but is disappointed that the overall rate of cancer deaths is not falling nearly enough.
"The rate of cancer diagnoses and deaths across all racial and minority groups are slowly decreasing," said Benz. "But there are still gaps that must be addressed."
The report is co-authored by researchers from the Centers for Disease Control and Prevention, the North American Association of Central Cancer Registries, the National Cancer Institute, and the American Cancer Society. It will be posted on the web site of the journal CANCER on March 28, 2012.
Among children ages 19 years or younger, the report shows cancer incidence rates increased 0.6 percent per year from 2004 through 2008, while death rates decreased 1.3 percent per year during the same period.
The authors also highlighted cancers associated with excess weight and lack of sufficient physical activity.
"This report emphasizes that the growing obesity problem and decreased overall physical activity in our society compared to decades ago have a real impact on multiple diseases, including cancer," said Jeffrey A. Meyerhardt, MD, MPH, a colorectal cancer expert at Dana-Farber and author of several studies investigating the impact of exercise on survival rates for colorectal cancer patients. "While we currently see declines in incidence of many cancers, if obesity continues at the current rates, I believe these improvements in incidence will reverse and increase over time."
Benz added that the good news is that some of the cancer risks the report highlighted can be reduced by changes in lifestyle.
"Many of the things that are still a problem in these statistics are modifiable," said Benz. "If you watch your diet, exercise, and manage your weight, you can not only prevent your risk of getting many lethal forms of cancer, you will also increase your chances of doing well, if you should get almost any form of cancer."
The report also finds that the overall rate of new cancer diagnoses for men and women combined decreased an average of less than one percent per year from 1998 through 2006, with rates leveling off from 2006 through 2008. Edward J. Benz, Jr., MD, president of Dana-Farber Cancer Institute in Boston, called the news encouraging, but is disappointed that the overall rate of cancer deaths is not falling nearly enough.
"The rate of cancer diagnoses and deaths across all racial and minority groups are slowly decreasing," said Benz. "But there are still gaps that must be addressed."
The report is co-authored by researchers from the Centers for Disease Control and Prevention, the North American Association of Central Cancer Registries, the National Cancer Institute, and the American Cancer Society. It will be posted on the web site of the journal CANCER on March 28, 2012.
Among children ages 19 years or younger, the report shows cancer incidence rates increased 0.6 percent per year from 2004 through 2008, while death rates decreased 1.3 percent per year during the same period.
The authors also highlighted cancers associated with excess weight and lack of sufficient physical activity.
"This report emphasizes that the growing obesity problem and decreased overall physical activity in our society compared to decades ago have a real impact on multiple diseases, including cancer," said Jeffrey A. Meyerhardt, MD, MPH, a colorectal cancer expert at Dana-Farber and author of several studies investigating the impact of exercise on survival rates for colorectal cancer patients. "While we currently see declines in incidence of many cancers, if obesity continues at the current rates, I believe these improvements in incidence will reverse and increase over time."
Benz added that the good news is that some of the cancer risks the report highlighted can be reduced by changes in lifestyle.
"Many of the things that are still a problem in these statistics are modifiable," said Benz. "If you watch your diet, exercise, and manage your weight, you can not only prevent your risk of getting many lethal forms of cancer, you will also increase your chances of doing well, if you should get almost any form of cancer."
Friday, April 13, 2012
Commonly used diabetes drug may help to prevent liver cancer
Metformin, a drug widely used to treat Type II diabetes, may help to prevent primary liver cancer, researchers at the University of Maryland Marlene and Stewart Greenebaum Cancer Center report in the April 1, 2012, issue of Cancer Prevention Research. Primary liver cancer, or hepatocellular carcinoma, is an often-deadly form of cancer that is on the rise worldwide and is the fastest-growing cause of cancer-related deaths among American men.
Patients with Type II diabetes have a two- to three-fold increased relative risk of developing primary liver cancer. Also at risk are people who are obese, have hepatitis or non-alcoholic fatty liver disease (NAFLD). Metformin, which is derived from the French lilac, is used to treat NAFLD as well as diabetes, and currently is being studied in connection with the prevention of a variety of cancers. This pre-clinical study is the first to focus on liver cancer.
"Our research demonstrated that metformin prevents primary liver cancer in animal models. Mice treated with metformin had significantly smaller and fewer tumors than those who did not receive the medication," says the study's senior author, Geoffrey D. Girnun, Ph.D., assistant professor of biochemistry and molecular biology at the University of Maryland School of Medicine and a researcher at the University of Maryland Greenebaum Cancer Center. "Based on these findings, we believe metformin should be evaluated as a preventive agent in people who are at high risk. Many patients with diabetes already are taking this medication, with few side effects."
Dr. Girnun adds, "There have been several retrospective epidemiological studies linking metformin with reduced risk of liver cancer, but our study is the first to formally test whether metformin can protect against carcinogenesis -- not just tumor growth and development, but actual tumor formation in the liver." He says he will seek federal funding for a clinical trial to study the anti-cancer effects of metformin in patients who have Type II diabetes.
E. Albert Reece, M.D., Ph.D., M.B.A., vice president of medical affairs at the University of Maryland and dean of the University of Maryland School of Medicine, says, "Hepatocellular carcinoma represents a serious public health threat worldwide. With the alarming increases in obesity, Type II diabetes and hepatitis B and C, an even greater number of people will be at risk of developing this cancer in the future. Not only do we need to find more effective treatments, we must also find ways to prevent it. This study conducted by Dr. Girnun and his colleagues is an excellent first step that may ultimately help us to prevent liver cancer in targeted populations."
Kevin J. Cullen, M.D., professor of medicine at the University of Maryland School of Medicine and director of the University of Maryland Greenebaum Cancer Center, says, "This study increases our knowledge of cancer cell metabolism and offers new insights into a possible mechanism for preventing a difficult-to-treat cancer. Translational research is an important focus of our cancer center, and we plan to continue this important area of research as part of a clinical study to determine if there is a possible benefit to patients."
The study is featured on the cover of Cancer Prevention Research, a journal published by the American Association for Cancer Research. Kavita Bhalla, Ph.D., a postdoctoral fellow at the University of Maryland School of Medicine and a Greenebaum Cancer Center researcher, is the lead author.
Glucose is converted into fatty acids in the liver through a process called lipogenesis. This process is increased in people who have diabetes, hepatitis, fatty liver disease as well as cancer. Dr. Girnun says metformin reduces the level of glucose and inhibits this fatty acid synthesis. "When you block this process, you prevent the cells from making more building blocks to make more cells. There is also no energy to put the building blocks together, and the cells are not able to proliferate, thereby preventing tumors from developing," he explains.
In the study, researchers found that mice treated with metformin in their food developed 57 percent fewer liver tumors than the mice that did not receive the drug; the size of the tumors was reduced by about 37 percent.
Patients with Type II diabetes have a two- to three-fold increased relative risk of developing primary liver cancer. Also at risk are people who are obese, have hepatitis or non-alcoholic fatty liver disease (NAFLD). Metformin, which is derived from the French lilac, is used to treat NAFLD as well as diabetes, and currently is being studied in connection with the prevention of a variety of cancers. This pre-clinical study is the first to focus on liver cancer.
"Our research demonstrated that metformin prevents primary liver cancer in animal models. Mice treated with metformin had significantly smaller and fewer tumors than those who did not receive the medication," says the study's senior author, Geoffrey D. Girnun, Ph.D., assistant professor of biochemistry and molecular biology at the University of Maryland School of Medicine and a researcher at the University of Maryland Greenebaum Cancer Center. "Based on these findings, we believe metformin should be evaluated as a preventive agent in people who are at high risk. Many patients with diabetes already are taking this medication, with few side effects."
Dr. Girnun adds, "There have been several retrospective epidemiological studies linking metformin with reduced risk of liver cancer, but our study is the first to formally test whether metformin can protect against carcinogenesis -- not just tumor growth and development, but actual tumor formation in the liver." He says he will seek federal funding for a clinical trial to study the anti-cancer effects of metformin in patients who have Type II diabetes.
E. Albert Reece, M.D., Ph.D., M.B.A., vice president of medical affairs at the University of Maryland and dean of the University of Maryland School of Medicine, says, "Hepatocellular carcinoma represents a serious public health threat worldwide. With the alarming increases in obesity, Type II diabetes and hepatitis B and C, an even greater number of people will be at risk of developing this cancer in the future. Not only do we need to find more effective treatments, we must also find ways to prevent it. This study conducted by Dr. Girnun and his colleagues is an excellent first step that may ultimately help us to prevent liver cancer in targeted populations."
Kevin J. Cullen, M.D., professor of medicine at the University of Maryland School of Medicine and director of the University of Maryland Greenebaum Cancer Center, says, "This study increases our knowledge of cancer cell metabolism and offers new insights into a possible mechanism for preventing a difficult-to-treat cancer. Translational research is an important focus of our cancer center, and we plan to continue this important area of research as part of a clinical study to determine if there is a possible benefit to patients."
The study is featured on the cover of Cancer Prevention Research, a journal published by the American Association for Cancer Research. Kavita Bhalla, Ph.D., a postdoctoral fellow at the University of Maryland School of Medicine and a Greenebaum Cancer Center researcher, is the lead author.
Glucose is converted into fatty acids in the liver through a process called lipogenesis. This process is increased in people who have diabetes, hepatitis, fatty liver disease as well as cancer. Dr. Girnun says metformin reduces the level of glucose and inhibits this fatty acid synthesis. "When you block this process, you prevent the cells from making more building blocks to make more cells. There is also no energy to put the building blocks together, and the cells are not able to proliferate, thereby preventing tumors from developing," he explains.
In the study, researchers found that mice treated with metformin in their food developed 57 percent fewer liver tumors than the mice that did not receive the drug; the size of the tumors was reduced by about 37 percent.
Thursday, April 12, 2012
Metformin may protect you against liver cancer
Metformin, a widely used, well-tolerated drug prescribed for patients with diabetes, may protect against liver cancer, according to a study published in Cancer Prevention Research, a journal of the American Association for Cancer Research.
The study, led by Geoffrey Girnun, Ph.D., an assistant professor in the department of biochemistry and molecular biology at the University of Maryland School of Medicine, is one more in an ongoing look at the effect of metformin in cancer prevention. However, it is one of the first to evaluate liver cancer.
"Since many of the effects of the drug take place in the liver, we were surprised when we reviewed the literature that there was no direct evidence for a protective effect of metformin in liver cancer except for a few retrospective epidemiological studies," said Girnun.
He and his colleagues chemically induced liver tumors in mice. The mice taking metformin displayed minimal tumor activity, while the control mice displayed significant tumor growth.
Girnun's team also showed that metformin prevented liver cancer in part by inhibiting lipid synthesis in the liver, a process known to promote cancer. Patients with diabetes, obese individuals, patients with hepatitis or patients with nonalcoholic fatty liver disease are at the greatest risk for liver cancer. All these diseases are associated with increased lipid synthesis. While diabetic patients are already prescribed metformin for their conditions, according to Girnun, the mechanism by which metformin prevents liver cancer may be transferable to these other patient populations at risk for liver cancer.
"So we are talking about a targeted population that will receive this benefit," he said.
Girnun is currently planning a clinical trial in patients at risk for liver cancer to determine if the chemopreventive qualities observed in mice are confirmed in humans.
The study, led by Geoffrey Girnun, Ph.D., an assistant professor in the department of biochemistry and molecular biology at the University of Maryland School of Medicine, is one more in an ongoing look at the effect of metformin in cancer prevention. However, it is one of the first to evaluate liver cancer.
"Since many of the effects of the drug take place in the liver, we were surprised when we reviewed the literature that there was no direct evidence for a protective effect of metformin in liver cancer except for a few retrospective epidemiological studies," said Girnun.
He and his colleagues chemically induced liver tumors in mice. The mice taking metformin displayed minimal tumor activity, while the control mice displayed significant tumor growth.
Girnun's team also showed that metformin prevented liver cancer in part by inhibiting lipid synthesis in the liver, a process known to promote cancer. Patients with diabetes, obese individuals, patients with hepatitis or patients with nonalcoholic fatty liver disease are at the greatest risk for liver cancer. All these diseases are associated with increased lipid synthesis. While diabetic patients are already prescribed metformin for their conditions, according to Girnun, the mechanism by which metformin prevents liver cancer may be transferable to these other patient populations at risk for liver cancer.
"So we are talking about a targeted population that will receive this benefit," he said.
Girnun is currently planning a clinical trial in patients at risk for liver cancer to determine if the chemopreventive qualities observed in mice are confirmed in humans.
Wednesday, April 11, 2012
Experts say that whole genome sequencing not informative for all
With sharp declines in the cost of whole genome sequencing, the day of accurately deciphering disease risk based on an individual's genome may seem at hand. But a study involving data of thousands of identical twins by Johns Hopkins investigators finds that genomic fortune-telling fails to provide informative guidance to most people about their risk for most common diseases, and warns against complacency born of negative genome test results.
Findings from the Johns Hopkins researchers' evaluation of the predictive value of whole genome sequencing are published online April 2 in Science Translational Medicine.
Whole genomic sequencing catalogs all of the genes that a person inherits from each parent. On average, any two individuals' genomes differ in 4.5million positions scattered throughout their genomes. Whole genome sequencing identifies those differences and links them to known or suspected contributions to an individual's risk of certain diseases.
The Johns Hopkins research casts doubt on whether whole genome sequencing can reliably predict the majority of future medical problems that will be encountered by most people who take such tests.
"We believe that genomic tests will not be substitutes for current disease prevention strategies," says Bert Vogelstein, M.D., Clayton Professor of Oncology at the Johns Hopkins Kimmel Cancer Center, co-director of the Ludwig Center for Cancer Genetics, and investigator of the Howard Hughes Medical Institute. "Prudent screening, early diagnosis and prevention strategies, such as not smoking and removing early cancers, will be the keys to cutting disease death rates."
To investigate the predictive potential of whole genome sequencing, the Johns Hopkins team used data recorded on thousands of identical twins entered into registries in Sweden, Denmark, Finland, Norway and the National Academy of Science's National Research World War II Veterans Twins Registry. "Identical twins share the same genome, and if the genome were the determining factor for common diseases, then the prevalence of a specific disease in an individual whose twin has that disease can be used to determine how well whole genome sequencing could predict an individual's disease risk," says Vogelstein.
The Johns Hopkins team collected information on the incidence of 24 diseases among the twin-pair groups, including cancer, as well as autoimmune, cardiovascular, genitourinary, neurological and obesity-associated diseases. To predict disease risk, they used mathematical models designed by Johns Hopkins graduate student Nicholas Roberts, D.V.M., and Joshua Vogelstein, Ph.D., assistant research scientist at the Johns Hopkins University Whiting School of Engineering and Bert Vogelstein's son, in collaboration with Giovanni Parmigiani, Ph.D., professor of biostatistics and computational biology at the Dana-Farber Cancer Institute. The models were used to calculate the capacity of whole genome sequencing to predict the risk of each disease based on typical thresholds used by doctors to initiate preventive or therapeutic measures.
Their analysis shows that whole genome sequencing could alert most individuals to an increased risk of at least one disease, signaled by a positive test result, but most people would get negative test results for the majority of diseases studied, failing to forewarn them of the diseases they may ultimately develop.
Kenneth Kinzler, Ph.D., co-director of the Ludwig Center at Johns Hopkins and professor of oncology, provides an example of what their analysis showed: "As many as two percent of women undergoing whole genome sequencing could receive a positive test result for ovarian cancer, alerting them that they have at least a one-in-ten chance of developing that cancer over their lifetime. The other 98 percent of women who receive a negative test for ovarian cancer will not be guaranteed a lifetime free of ovarian cancer because their risk of developing it is very similar to that of the general population. So, a negative test is not a 'free pass' to discount the chance of acquiring any particular disease."
The investigators say their analysis specifically shows that whole-genome-based tests are not highly informative for predicting cancer in most individuals without a strong family history of the disease. On the other hand, genetic tests could identify, theoretically, more than three-quarters of patients who may develop four of the diseases studied -- coronary heart disease in men, thyroid autoimmunity, type 1 diabetes and Alzheimer's disease.
"In families with strong histories of cancer, whole genome sequencing can still be very informative for identifying inherited genes that increase cancer risk," says Victor Velculescu, M.D., Ph.D., professor of oncology, who with Vogelstein and Kinzler provided some of the first evidence that inherited pancreatic cancer genes can be identified in families through whole genome sequencing. "But hereditary cancers are rare. Most cancers arise from mutations acquired through environmental exposures, lifestyle choices and random mistakes in genes that occur when cells divide."
Funding for the study was provided by the Lustgarten Foundation for Pancreatic Cancer Research, the Virginia and D.K. Ludwig Fund for Cancer Research, National Institutes of Health, an AACR Stand Up to Cancer-Dream Team Translational Cancer Research Grant, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation and the European Community's Seventh Framework Programme.
Vogelstein, Kinzler and Velculescu are co-founders and Scientific Advisory Board members of Inostics and Personal Genome Diagnostics. They own Inostics and Personal Genome Diagnostics stock, which is subject to certain restrictions under Johns Hopkins University policy. The terms of these arrangements are being managed by the Johns Hopkins University in accordance with its conflict-of-interest policies.
Findings from the Johns Hopkins researchers' evaluation of the predictive value of whole genome sequencing are published online April 2 in Science Translational Medicine.
Whole genomic sequencing catalogs all of the genes that a person inherits from each parent. On average, any two individuals' genomes differ in 4.5million positions scattered throughout their genomes. Whole genome sequencing identifies those differences and links them to known or suspected contributions to an individual's risk of certain diseases.
The Johns Hopkins research casts doubt on whether whole genome sequencing can reliably predict the majority of future medical problems that will be encountered by most people who take such tests.
"We believe that genomic tests will not be substitutes for current disease prevention strategies," says Bert Vogelstein, M.D., Clayton Professor of Oncology at the Johns Hopkins Kimmel Cancer Center, co-director of the Ludwig Center for Cancer Genetics, and investigator of the Howard Hughes Medical Institute. "Prudent screening, early diagnosis and prevention strategies, such as not smoking and removing early cancers, will be the keys to cutting disease death rates."
To investigate the predictive potential of whole genome sequencing, the Johns Hopkins team used data recorded on thousands of identical twins entered into registries in Sweden, Denmark, Finland, Norway and the National Academy of Science's National Research World War II Veterans Twins Registry. "Identical twins share the same genome, and if the genome were the determining factor for common diseases, then the prevalence of a specific disease in an individual whose twin has that disease can be used to determine how well whole genome sequencing could predict an individual's disease risk," says Vogelstein.
The Johns Hopkins team collected information on the incidence of 24 diseases among the twin-pair groups, including cancer, as well as autoimmune, cardiovascular, genitourinary, neurological and obesity-associated diseases. To predict disease risk, they used mathematical models designed by Johns Hopkins graduate student Nicholas Roberts, D.V.M., and Joshua Vogelstein, Ph.D., assistant research scientist at the Johns Hopkins University Whiting School of Engineering and Bert Vogelstein's son, in collaboration with Giovanni Parmigiani, Ph.D., professor of biostatistics and computational biology at the Dana-Farber Cancer Institute. The models were used to calculate the capacity of whole genome sequencing to predict the risk of each disease based on typical thresholds used by doctors to initiate preventive or therapeutic measures.
Their analysis shows that whole genome sequencing could alert most individuals to an increased risk of at least one disease, signaled by a positive test result, but most people would get negative test results for the majority of diseases studied, failing to forewarn them of the diseases they may ultimately develop.
Kenneth Kinzler, Ph.D., co-director of the Ludwig Center at Johns Hopkins and professor of oncology, provides an example of what their analysis showed: "As many as two percent of women undergoing whole genome sequencing could receive a positive test result for ovarian cancer, alerting them that they have at least a one-in-ten chance of developing that cancer over their lifetime. The other 98 percent of women who receive a negative test for ovarian cancer will not be guaranteed a lifetime free of ovarian cancer because their risk of developing it is very similar to that of the general population. So, a negative test is not a 'free pass' to discount the chance of acquiring any particular disease."
The investigators say their analysis specifically shows that whole-genome-based tests are not highly informative for predicting cancer in most individuals without a strong family history of the disease. On the other hand, genetic tests could identify, theoretically, more than three-quarters of patients who may develop four of the diseases studied -- coronary heart disease in men, thyroid autoimmunity, type 1 diabetes and Alzheimer's disease.
"In families with strong histories of cancer, whole genome sequencing can still be very informative for identifying inherited genes that increase cancer risk," says Victor Velculescu, M.D., Ph.D., professor of oncology, who with Vogelstein and Kinzler provided some of the first evidence that inherited pancreatic cancer genes can be identified in families through whole genome sequencing. "But hereditary cancers are rare. Most cancers arise from mutations acquired through environmental exposures, lifestyle choices and random mistakes in genes that occur when cells divide."
Funding for the study was provided by the Lustgarten Foundation for Pancreatic Cancer Research, the Virginia and D.K. Ludwig Fund for Cancer Research, National Institutes of Health, an AACR Stand Up to Cancer-Dream Team Translational Cancer Research Grant, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation and the European Community's Seventh Framework Programme.
Vogelstein, Kinzler and Velculescu are co-founders and Scientific Advisory Board members of Inostics and Personal Genome Diagnostics. They own Inostics and Personal Genome Diagnostics stock, which is subject to certain restrictions under Johns Hopkins University policy. The terms of these arrangements are being managed by the Johns Hopkins University in accordance with its conflict-of-interest policies.
New research found out that a certain protein could stop tumour cells from spreading
Researchers from the Department of Chemistry and Molecular Biology at the University of Gothenburg have managed for the first time to obtain detailed information about the role of the protein metastasin in the spread of tumour cells. Published recently in Proceedings of the National Academy of Sciences (PNAS), the study paves the way for the development of new drugs.
Metastasin is a protein with a key role in the spread of tumour cells.
Previous research has shown that it is activated through the binding of calcium ions and then binds to and modulates other proteins.
Increases the spread of tumour cells
One of metastasin's binding partners is a motor protein called non-muscle myosin. Motor proteins are the driving force behind cell mobility. By binding to this protein, metastasin can increase the spread of tumour cells, acting as a kind of gas pedal for the cancer engine.
"Using a method called X-ray crystallography, we have managed for the first time to obtain detailed information on how metastasin binds to a motor protein, a process that facilitates the spread of tumour cells," explains researcher Gergely Katona.
Detailed picture
It has been possible to image metastasin and calcium-ion-bound metastasin using X-ray crystallography before, but the researchers at the University of Gothenburg are the first to have imaged the structure of calcium-ion-activated metastasin with an attached non-muscle myosin fragment.
"This has given us information about regions of both metastasin and the motor protein that are crucial for metastasin's ability to bind to the motor protein. This is important to know for drugs to be developed that block these specific regions and so prevent this binding."
The image of the two molecules gives us a better understanding of how metastasin binds to the motor protein, so increasing cell mobility and the spread of tumour cells. This understanding in turn paves the way for the development of new drugs to prevent this harmful interaction between molecules and so stop tumour cells from spreading.
"The metastasin and the motor protein can be imaged as a snapshot, but the next stage is to create a kind of video to see how the molecules move when binding to one another," explains Katona.
Metastasin is a protein with a key role in the spread of tumour cells.
Previous research has shown that it is activated through the binding of calcium ions and then binds to and modulates other proteins.
Increases the spread of tumour cells
One of metastasin's binding partners is a motor protein called non-muscle myosin. Motor proteins are the driving force behind cell mobility. By binding to this protein, metastasin can increase the spread of tumour cells, acting as a kind of gas pedal for the cancer engine.
"Using a method called X-ray crystallography, we have managed for the first time to obtain detailed information on how metastasin binds to a motor protein, a process that facilitates the spread of tumour cells," explains researcher Gergely Katona.
Detailed picture
It has been possible to image metastasin and calcium-ion-bound metastasin using X-ray crystallography before, but the researchers at the University of Gothenburg are the first to have imaged the structure of calcium-ion-activated metastasin with an attached non-muscle myosin fragment.
"This has given us information about regions of both metastasin and the motor protein that are crucial for metastasin's ability to bind to the motor protein. This is important to know for drugs to be developed that block these specific regions and so prevent this binding."
The image of the two molecules gives us a better understanding of how metastasin binds to the motor protein, so increasing cell mobility and the spread of tumour cells. This understanding in turn paves the way for the development of new drugs to prevent this harmful interaction between molecules and so stop tumour cells from spreading.
"The metastasin and the motor protein can be imaged as a snapshot, but the next stage is to create a kind of video to see how the molecules move when binding to one another," explains Katona.
Tuesday, April 10, 2012
Body Mass Index (BMI) Not Found To Play A Role In Surgical Complications Or In Survival
Researchers at Moffitt Cancer Center in Tampa, Fla., have found - contrary to previous studies linking inferior outcomes in patients with gastrointestinal malignancies to higher BMI - that in their study of BMI and negative outcomes, there was no such link. They concluded that BMI was not associated with either surgical complications or esophageal cancer patient survival.
Their study was published in the current online issue of the Journal of Gastrointestinal Surgery, published by the Society for Surgery of the Alimentary Tract.
"The incidence of esophageal cancer in North America is rising," said study co-author Kenneth L. Meredith, M.D., assistant member at Moffitt and chief of the Esophagogastric Oncology Section. "Corresponding to that rise, there has been a dramatic rise in overweight and obese people as defined by the World Health Organization's guidelines indicating those having a BMI of 25 to 29.9 as being overweight and those who are obese as having a BMI of over 30."
According to the researchers, the increase in obesity and the increase in esophageal cancer has been linked, as has obesity been similarly linked with other kinds of cancers. Obesity is recognized as a risk factor for esophageal cancer. What remains in question, however, is whether a high BMI affects post-surgical complications and overall survival among esophageal cancer patients who have been treated with chemotherapy, radiation and surgery.
"The correlation of obesity with surgical risks and postoperative survival is more important given the rise in obesity rates, yet more clarity on potential correlation is needed," said Meredith. "The literature shows mixed study results."
In their paper, the authors cited a number of studies that correlated lower BMI with better outcomes for a variety of cancers as well as studies that found no prognostic significance correlating higher BMI with poorer outcomes.
Because of the prevailing belief that patients with a high BMI tend to have more surgical complications as compared to normal weight patients, the Moffitt researchers examined esophageal cancer patient data on BMI for links to surgical risk and postoperative survival, especially for those patients with high BMI.
Their study included 303 esophageal cancer patients treated with chemotherapy, radiation and surgery who were stratified by their BMI to include those with BMIs less than 25 to greater than 35. The only demographic differences were in gender, with a higher proportion of males in the BMI 25 to 30 group.
"Our study demonstrated no significant differences in overall survival or disease-free survival in relation to BMI for patients with esophageal adenocarcinoma who underwent surgery after prior treatment with chemotherapy and radiation," said Meredith. "Additionally, there were no differences in perioperative complications or mortality associated with BMI. In short, our data failed to demonstrate a link between BMI and surgical outcome."
Their study was published in the current online issue of the Journal of Gastrointestinal Surgery, published by the Society for Surgery of the Alimentary Tract.
"The incidence of esophageal cancer in North America is rising," said study co-author Kenneth L. Meredith, M.D., assistant member at Moffitt and chief of the Esophagogastric Oncology Section. "Corresponding to that rise, there has been a dramatic rise in overweight and obese people as defined by the World Health Organization's guidelines indicating those having a BMI of 25 to 29.9 as being overweight and those who are obese as having a BMI of over 30."
According to the researchers, the increase in obesity and the increase in esophageal cancer has been linked, as has obesity been similarly linked with other kinds of cancers. Obesity is recognized as a risk factor for esophageal cancer. What remains in question, however, is whether a high BMI affects post-surgical complications and overall survival among esophageal cancer patients who have been treated with chemotherapy, radiation and surgery.
"The correlation of obesity with surgical risks and postoperative survival is more important given the rise in obesity rates, yet more clarity on potential correlation is needed," said Meredith. "The literature shows mixed study results."
In their paper, the authors cited a number of studies that correlated lower BMI with better outcomes for a variety of cancers as well as studies that found no prognostic significance correlating higher BMI with poorer outcomes.
Because of the prevailing belief that patients with a high BMI tend to have more surgical complications as compared to normal weight patients, the Moffitt researchers examined esophageal cancer patient data on BMI for links to surgical risk and postoperative survival, especially for those patients with high BMI.
Their study included 303 esophageal cancer patients treated with chemotherapy, radiation and surgery who were stratified by their BMI to include those with BMIs less than 25 to greater than 35. The only demographic differences were in gender, with a higher proportion of males in the BMI 25 to 30 group.
"Our study demonstrated no significant differences in overall survival or disease-free survival in relation to BMI for patients with esophageal adenocarcinoma who underwent surgery after prior treatment with chemotherapy and radiation," said Meredith. "Additionally, there were no differences in perioperative complications or mortality associated with BMI. In short, our data failed to demonstrate a link between BMI and surgical outcome."
Monday, April 9, 2012
Study shows that protection against skin cancer caused by sun exposure may be found in caffeine and excercise
The combined effects of exercise plus caffeine consumption may be able to ward off skin cancer and also prevent inflammation related to other obesity-linked cancers.
"We found that this combination treatment can decrease sunlight-caused skin cancer formation in a mouse model," said Yao-Ping Lu, Ph.D., associate research professor of chemical biology and director of skin cancer prevention at the Rutgers Ernest Mario School of Pharmacy in Piscataway, N.J. He presented these findings at the AACR Annual Meeting 2012, held in Chicago March 31 -- April 4.
"I believe we may extrapolate these findings to humans and anticipate that we would benefit from these combination treatments as well," Lu added.
The researchers evaluated the effects of caffeine and exercise on mice at high risk for developing skin cancer. Results showed that mice that took a dose of caffeine and exercised with a running wheel experienced 62 percent fewer skin tumors. The volume of tumors also decreased by 85 percent compared with the mice that did not consume caffeine or exercise.
Positive effects were found with either caffeine or exercise alone, but to a lesser extent. Researchers observed a 27 percent reduction in tumors in caffeine-only mice and a 61 percent reduction in tumor size. In the exercise-only mice, researchers found that tumor activity decreased by 35 percent and tumor volume decreased by 70 percent.
The researchers also found that exercise and caffeine reduced weight and inflammation. They fed mice a high-fat diet of omega-6 fatty acid-rich foods and measured the volume of the parametrial fat pad (the largest fat pad in a mouse) after two weeks of exercise and/or caffeine treatment.
Mice that had caffeine and exercised had a fat pad weight decrease of 63 percent. Caffeine-only mice had a 30 percent decrease, and exercise-only mice had a 56 percent decrease. Development and size of cancer decreased as well. The link, Lu believes, is inflammation, which dropped as much as 92 percent in mice that exercised and consumed caffeine.
"We found that this combination treatment can decrease sunlight-caused skin cancer formation in a mouse model," said Yao-Ping Lu, Ph.D., associate research professor of chemical biology and director of skin cancer prevention at the Rutgers Ernest Mario School of Pharmacy in Piscataway, N.J. He presented these findings at the AACR Annual Meeting 2012, held in Chicago March 31 -- April 4.
"I believe we may extrapolate these findings to humans and anticipate that we would benefit from these combination treatments as well," Lu added.
The researchers evaluated the effects of caffeine and exercise on mice at high risk for developing skin cancer. Results showed that mice that took a dose of caffeine and exercised with a running wheel experienced 62 percent fewer skin tumors. The volume of tumors also decreased by 85 percent compared with the mice that did not consume caffeine or exercise.
Positive effects were found with either caffeine or exercise alone, but to a lesser extent. Researchers observed a 27 percent reduction in tumors in caffeine-only mice and a 61 percent reduction in tumor size. In the exercise-only mice, researchers found that tumor activity decreased by 35 percent and tumor volume decreased by 70 percent.
The researchers also found that exercise and caffeine reduced weight and inflammation. They fed mice a high-fat diet of omega-6 fatty acid-rich foods and measured the volume of the parametrial fat pad (the largest fat pad in a mouse) after two weeks of exercise and/or caffeine treatment.
Mice that had caffeine and exercised had a fat pad weight decrease of 63 percent. Caffeine-only mice had a 30 percent decrease, and exercise-only mice had a 56 percent decrease. Development and size of cancer decreased as well. The link, Lu believes, is inflammation, which dropped as much as 92 percent in mice that exercised and consumed caffeine.
Sunday, April 8, 2012
Blueprint for new drugs that can inhibit hepatitis C virus discovered
Chemists at the University of California, San Diego have produced the first high resolution structure of a molecule that when attached to the genetic material of the hepatitis C virus prevents it from reproducing.
Hepatitis C is a chronic infectious disease that affects some 170 million people worldwide and causes chronic liver disease and liver cancer. According to the Centers for Disease Control and Prevention, hepatitis C now kills more Americans each year than HIV.
The structure of the molecule, which was published in a paper in this week's early online edition of the journal Proceedings of the National Academy of Sciences, provides a detailed blueprint for the design of drugs that can inhibit the replication of the hepatitis C virus, which proliferates by hijacking the cellular machinery in humans to manufacture duplicate viral particles.
Finding a way to stop that process could effectively treat viral infections of hepatitis C, for which no vaccine is currently available. But until now scientists have identified few inhibiting compounds that directly act on the virus's ribonucleic acid (RNA) genome -- the organism's full complement of genetic material.
"This lack of detailed information on how inhibitors lock onto the viral genome target has hampered the development of better drugs," said Thomas Hermann, an associate professor of chemistry and biochemistry at UC San Diego who headed the research team, which also included scientists from San Diego State University. The team detailed the structure of a molecule that induces the viral RNA to open up a portion of its hinge-like structure and encapsulate the inhibitor like a perfectly fit glove, blocking the ability of the hepatitis C virus to replicate.
The molecule is from a class of compounds called benzimidazoles, known to stop the production of viral proteins in infected human cells. Its three-dimensional atomic structure was determined by X-ray crystallography, a method of mapping the arrangement of atoms within a crystal, in which a beam of X-rays strikes a crystal and causes the beam of light to spread. The angles and intensities of the light beams allowed the scientists to calculate the structure of the viral RNA-inhibitor complex.
"This structure will guide approaches to rationally design better drug candidates and improve the known benzimidazole inhibitors," said Hermann. "Also, the crystal structure demonstrates that the binding pocket for the inhibitors in the hepatitis C virus RNA resembles drug-binding pockets in proteins. This is important to help overcome the notion that RNA targets are so unlike traditional protein targets that drug discovery approaches with small molecule inhibitors are difficult to achieve for RNA."
Hepatitis C is a chronic infectious disease that affects some 170 million people worldwide and causes chronic liver disease and liver cancer. According to the Centers for Disease Control and Prevention, hepatitis C now kills more Americans each year than HIV.
The structure of the molecule, which was published in a paper in this week's early online edition of the journal Proceedings of the National Academy of Sciences, provides a detailed blueprint for the design of drugs that can inhibit the replication of the hepatitis C virus, which proliferates by hijacking the cellular machinery in humans to manufacture duplicate viral particles.
Finding a way to stop that process could effectively treat viral infections of hepatitis C, for which no vaccine is currently available. But until now scientists have identified few inhibiting compounds that directly act on the virus's ribonucleic acid (RNA) genome -- the organism's full complement of genetic material.
"This lack of detailed information on how inhibitors lock onto the viral genome target has hampered the development of better drugs," said Thomas Hermann, an associate professor of chemistry and biochemistry at UC San Diego who headed the research team, which also included scientists from San Diego State University. The team detailed the structure of a molecule that induces the viral RNA to open up a portion of its hinge-like structure and encapsulate the inhibitor like a perfectly fit glove, blocking the ability of the hepatitis C virus to replicate.
The molecule is from a class of compounds called benzimidazoles, known to stop the production of viral proteins in infected human cells. Its three-dimensional atomic structure was determined by X-ray crystallography, a method of mapping the arrangement of atoms within a crystal, in which a beam of X-rays strikes a crystal and causes the beam of light to spread. The angles and intensities of the light beams allowed the scientists to calculate the structure of the viral RNA-inhibitor complex.
"This structure will guide approaches to rationally design better drug candidates and improve the known benzimidazole inhibitors," said Hermann. "Also, the crystal structure demonstrates that the binding pocket for the inhibitors in the hepatitis C virus RNA resembles drug-binding pockets in proteins. This is important to help overcome the notion that RNA targets are so unlike traditional protein targets that drug discovery approaches with small molecule inhibitors are difficult to achieve for RNA."
Higher risk of breast cancer linked to long-term use of estrogen hormone therapy
In a landmark study, researchers have linked the long-term use of estrogen plus progesterone and estrogen-only hormone therapy with a higher risk for developing breast cancer.
"It's already been confirmed that patients shouldn't be undergoing estrogen plus progesterone hormone therapy (HT) for the long term," said Wendy Y. Chen, M.D., M.P.H., associate physician at Brigham and Women's Hospital and assistant professor in medicine at the Breast Cancer Oncology Center at the Dana-Farber Cancer Institute in Boston, Mass. "What we found is that people should also be careful about longer-term use of estrogen-alone HT."
In previous studies, she said, researchers only evaluated risks associated with less than 10 years of HT use. Chen presented the findings at the AACR Annual Meeting 2012, held in Chicago March 31 -- April 4.
Using data from the Nurses' Health Study, the researchers evaluated follow-up data collected during 1980 through 2008 from postmenopausal female registered nurses who were aged 30 to 55 years old in 1976.
Chen and colleagues found that the risk for breast cancer, when compared with women who did not use HT, was 88 percent higher in women who had taken estrogen plus progesterone for 10 to 14.9 years; the risk increased more than twofold for women who used estrogen plus progesterone therapy for 15 to 19.9 years. For women who used estrogen-only HT, researchers found a 22 percent increased risk for breast cancer if used for 10 to 14.9 years and a 43 percent greater risk associated with 15 to 19.9 years of use.
Researchers also found that the risk did not plateau for either kind of HT. "There's a continued effect over time. The longer you use it, the higher the risk," said Chen.
To further clarify long-term risks of estrogen-only therapy, the researchers evaluated a subset of the women who also met the requirements of participants in the Women's Health Initiative trial, which is a randomized trial of postmenopausal women aged 50 years or older. Although the risk for breast cancer dipped slightly for women who used estrogen-only HT for less than 10 years, the risk increased 30 percent for women who took estrogen for 15 to 19.9 years.
HT did not increase the risk for fatal breast cancers.
"Even though we saw an increased risk in developing breast cancer, we did not see an increased risk for dying from breast cancer," Chen said. She and her colleagues are currently researching this aspect of the findings.
"It's already been confirmed that patients shouldn't be undergoing estrogen plus progesterone hormone therapy (HT) for the long term," said Wendy Y. Chen, M.D., M.P.H., associate physician at Brigham and Women's Hospital and assistant professor in medicine at the Breast Cancer Oncology Center at the Dana-Farber Cancer Institute in Boston, Mass. "What we found is that people should also be careful about longer-term use of estrogen-alone HT."
In previous studies, she said, researchers only evaluated risks associated with less than 10 years of HT use. Chen presented the findings at the AACR Annual Meeting 2012, held in Chicago March 31 -- April 4.
Using data from the Nurses' Health Study, the researchers evaluated follow-up data collected during 1980 through 2008 from postmenopausal female registered nurses who were aged 30 to 55 years old in 1976.
Chen and colleagues found that the risk for breast cancer, when compared with women who did not use HT, was 88 percent higher in women who had taken estrogen plus progesterone for 10 to 14.9 years; the risk increased more than twofold for women who used estrogen plus progesterone therapy for 15 to 19.9 years. For women who used estrogen-only HT, researchers found a 22 percent increased risk for breast cancer if used for 10 to 14.9 years and a 43 percent greater risk associated with 15 to 19.9 years of use.
Researchers also found that the risk did not plateau for either kind of HT. "There's a continued effect over time. The longer you use it, the higher the risk," said Chen.
To further clarify long-term risks of estrogen-only therapy, the researchers evaluated a subset of the women who also met the requirements of participants in the Women's Health Initiative trial, which is a randomized trial of postmenopausal women aged 50 years or older. Although the risk for breast cancer dipped slightly for women who used estrogen-only HT for less than 10 years, the risk increased 30 percent for women who took estrogen for 15 to 19.9 years.
HT did not increase the risk for fatal breast cancers.
"Even though we saw an increased risk in developing breast cancer, we did not see an increased risk for dying from breast cancer," Chen said. She and her colleagues are currently researching this aspect of the findings.
Saturday, April 7, 2012
Breast cancer susceptibility gene
Mutations in a gene called XRCC2 cause increased breast cancer risk, according to a study published March 29 in the American Journal of Human Genetics. The study looked at families that have a history of the disease but do not have mutations in the currently known breast cancer susceptibility genes.
Sean Tavtigian, Ph.D., a Huntsman Cancer Institute (HCI) investigator and associate professor in the Department of Oncological Sciences at the University of Utah (U of U) is one of three co-principal investigators on the study, along with David Goldgar, Ph.D., professor in the Department of Dermatology at the U of U and an HCI investigator, and Melissa Southey, Ph.D., professor in the Department of Pathology at the University of Melbourne, Australia.
"We have added to the list of genes that harbour mutations causing breast cancer," said Tavtigian. "This knowledge will improve breast cancer diagnostics and add years to patients' lives. More important, relatives who have not been affected by the disease but carry the mutations will benefit even more. They can find out they are at risk before they have cancer and take action to reduce their risk or catch the cancer early."
XRCC2 may also provide a new target for chemotherapy. "A type of drug called a PARP inhibitor appears to kill tumor cells that have gene mutations in a particular DNA repair pathway. XRCC2 is in this pathway, as are BRCA1 and BRCA2. It's reasonably likely that a breast cancer patient who has a mutation in XRCC2 will respond well to treatment with PARP inhibitors," said Tavtigian.
According to Tavtigian, many breast cancer cases appear in families with a weak history of the disease. Only about 30 percent of the familial risk for breast cancer can be explained by a combination of mutations to and common sequence variation in the known breast cancer susceptibility genes. "So far most of the clinical diagnostic effort has been directed toward the very strong family history set of breast cancer cases and their close relatives," he said. "Our research looks at a population with a weaker family history, and as it turns out, a very rare gene mutation."
The researchers used a technology called exome capture massively parallel sequencing (exome sequencing), which shows the exact order of the nucleotides (the four building blocks of DNA) in all of the protein coding genes in the human genome. The ability of this technology to analyze the DNA of all of the genes in the genome in a single experiment, according to Tavtigian, makes it an amazingly powerful tool for genetic research. "We focused on the genes involved in a particular type of DNA repair, because most known breast cancer genes have been found there. That focused analysis allowed us to identify XRCC2 as a breast cancer susceptibility gene in individuals with a family history of breast cancer," says Tavtigian. "From the exome sequencing data, we found two different types of XRCC2 mutations that occur in breast cancer patients."
He explains that one type of mutation causes the gene to create an incomplete version of the protein. The resulting protein is usually dysfunctional. The other type occurs when a single amino acid in the protein is changed.
"It's a subtle change to the protein, but the resulting change in function could range anywhere from innocuous to even worse dysfunction than the incomplete protein causes," says Tavtigian. "Our sequence analyses suggest that we may have found the full spectrum of results in our study."
Further research is underway. "A worldwide effort has already been launched to figure out what fraction of breast cancer is due to mutations in this gene and how high the risk conferred by these mutations actually is," he says.
Sean Tavtigian, Ph.D., a Huntsman Cancer Institute (HCI) investigator and associate professor in the Department of Oncological Sciences at the University of Utah (U of U) is one of three co-principal investigators on the study, along with David Goldgar, Ph.D., professor in the Department of Dermatology at the U of U and an HCI investigator, and Melissa Southey, Ph.D., professor in the Department of Pathology at the University of Melbourne, Australia.
"We have added to the list of genes that harbour mutations causing breast cancer," said Tavtigian. "This knowledge will improve breast cancer diagnostics and add years to patients' lives. More important, relatives who have not been affected by the disease but carry the mutations will benefit even more. They can find out they are at risk before they have cancer and take action to reduce their risk or catch the cancer early."
XRCC2 may also provide a new target for chemotherapy. "A type of drug called a PARP inhibitor appears to kill tumor cells that have gene mutations in a particular DNA repair pathway. XRCC2 is in this pathway, as are BRCA1 and BRCA2. It's reasonably likely that a breast cancer patient who has a mutation in XRCC2 will respond well to treatment with PARP inhibitors," said Tavtigian.
According to Tavtigian, many breast cancer cases appear in families with a weak history of the disease. Only about 30 percent of the familial risk for breast cancer can be explained by a combination of mutations to and common sequence variation in the known breast cancer susceptibility genes. "So far most of the clinical diagnostic effort has been directed toward the very strong family history set of breast cancer cases and their close relatives," he said. "Our research looks at a population with a weaker family history, and as it turns out, a very rare gene mutation."
The researchers used a technology called exome capture massively parallel sequencing (exome sequencing), which shows the exact order of the nucleotides (the four building blocks of DNA) in all of the protein coding genes in the human genome. The ability of this technology to analyze the DNA of all of the genes in the genome in a single experiment, according to Tavtigian, makes it an amazingly powerful tool for genetic research. "We focused on the genes involved in a particular type of DNA repair, because most known breast cancer genes have been found there. That focused analysis allowed us to identify XRCC2 as a breast cancer susceptibility gene in individuals with a family history of breast cancer," says Tavtigian. "From the exome sequencing data, we found two different types of XRCC2 mutations that occur in breast cancer patients."
He explains that one type of mutation causes the gene to create an incomplete version of the protein. The resulting protein is usually dysfunctional. The other type occurs when a single amino acid in the protein is changed.
"It's a subtle change to the protein, but the resulting change in function could range anywhere from innocuous to even worse dysfunction than the incomplete protein causes," says Tavtigian. "Our sequence analyses suggest that we may have found the full spectrum of results in our study."
Further research is underway. "A worldwide effort has already been launched to figure out what fraction of breast cancer is due to mutations in this gene and how high the risk conferred by these mutations actually is," he says.
Friday, April 6, 2012
Scientists reprogram cancer cells with low doses of epigenetic drugs
Experimenting with cells in culture, researchers at the Johns Hopkins Kimmel Cancer Center have breathed possible new life into two drugs once considered too toxic for human cancer treatment. The drugs, azacitidine (AZA) and decitabine (DAC), are epigenetic-targeted drugs and work to correct cancer-causing alterations that modify DNA.
The researchers said the drugs also were found to take aim at a small but dangerous subpopulation of self-renewing cells, sometimes referred to as cancer stem cells, which evade most cancer drugs and cause recurrence and spread.
In a report published in the March 20, 2012, issue of Cancer Cell, the Johns Hopkins team said their study provides evidence that low doses of the drugs tested on cell cultures cause antitumor responses in breast, lung, and colon cancers.
Conventional chemotherapy agents work by indiscriminately poisoning and killing rapidly-dividing cells, including cancer cells, by damaging cellular machinery and DNA. "In contrast, low doses of AZA and DAC may re-activate genes that stop cancer growth without causing immediate cell-killing or DNA damage," says Stephen Baylin, M.D., Ludwig Professor of Oncology and deputy director of the Johns Hopkins Kimmel Cancer Center.
Many cancer experts had abandoned AZA and DAC for the treatment of common cancers, according to the researchers, because they are toxic to normal cells at standard high doses, and there was little research showing how they might work for cancer in general. Baylin and his colleague Cynthia Zahnow, Ph.D., decided to take another look at the drugs after low doses of the drugs showed a benefit in patients with a pre-leukemic disorder called myelodysplastic syndrome (MDS). Johns Hopkins investigators also showed benefit of low doses of the drugs in tests with a small number of advanced lung cancer patients. "This is contrary to the way we usually do things in cancer research," says Baylin, noting that "typically, we start in the laboratory and progress to clinical trials. In this case, we saw results in clinical trials that made us go back to the laboratory to figure out how to move the therapy forward."
For the research, Baylin and Zahnow's team worked with leukemia, breast, and other cancer cell lines and human tumor samples using the lowest possible doses that were effective against the cancers. In all, the investigators studied six leukemia cell lines, seven leukemia patient samples, three breast cancer cell lines, seven breast tumor samples (including four samples of tumors that had spread to the lung), one lung cancer tumor sample, and one colon cancer tumor sample. The team treated cell lines and tumor cells with low-dose AZA and DAC in culture for three days and allowed the drug-treated cells to rest for a week. Treated cells and tumor samples were then transplanted into mice where the researchers observed continued antitumor responses for up to 20 weeks. This extended response was in line with observations in some MDS patients who continued to have anticancer effects long after stopping the drug.
The low-dose therapy reversed cancer cell gene pathways, including those controlling cell cycle, cell repair, cell maturation, cell differentiation, immune cell interaction, and cell death. Effects varied among individual tumor cells, but the scientists generally saw that cancer cells reverted to a more normal state and eventually died. These results were caused, in part, by alteration of the epigenetic, or chemical environment, of DNA. Epigenetic activities turn on certain genes and block others, says Zahnow, assistant professor of oncology and the Evelyn Grolman Glick Scholar at Johns Hopkins.
The research team also tested AZA and DAC's effect on a type of metastatic breast cancer cell thought to drive cancer growth and resist standard therapies. Metastatic cells are difficult to study in standard laboratory tumor models, because they tend to break away from the original tumor and float around in blood and lymph fluids. The Johns Hopkins team re-created the metastatic stem cells' environment, allowing them to grow as floating spheres. "These cells were growing well as spheres in suspension, but when we treated the cells with AZA, both the size and number of spheres were dramatically reduced," says Zahnow.
The precise mechanism of how the drugs work is the focus of ongoing studies by Baylin and his team. "Our findings match evidence from recent clinical trials suggesting that the drugs shrink tumors more slowly over time as they repair altered mechanisms in cells and genes return to normal function and the cells may eventually die," says Baylin.
The results of clinical trials in lung cancer, led by Johns Hopkins' Charles Rudin, M.D., and published late last year in Cancer Discovery, also indicate that the drugs make tumors more responsive to standard anticancer drug treatment. This means, they say, that the drugs could become part of a combined treatment approach rather than a stand-alone therapy and as part of personalized approaches in patients whose cancers fit specific epigenetic and genetic profiles.
Low doses of both drugs are approved by the U.S. Food and Drug Administration for the treatment of MDS and chronic myelomonocytic leukemia (CMML). Clinical trials in breast and lung cancer have begun in patients with advanced disease, and trials in colon cancer are planned.
The researchers said the drugs also were found to take aim at a small but dangerous subpopulation of self-renewing cells, sometimes referred to as cancer stem cells, which evade most cancer drugs and cause recurrence and spread.
In a report published in the March 20, 2012, issue of Cancer Cell, the Johns Hopkins team said their study provides evidence that low doses of the drugs tested on cell cultures cause antitumor responses in breast, lung, and colon cancers.
Conventional chemotherapy agents work by indiscriminately poisoning and killing rapidly-dividing cells, including cancer cells, by damaging cellular machinery and DNA. "In contrast, low doses of AZA and DAC may re-activate genes that stop cancer growth without causing immediate cell-killing or DNA damage," says Stephen Baylin, M.D., Ludwig Professor of Oncology and deputy director of the Johns Hopkins Kimmel Cancer Center.
Many cancer experts had abandoned AZA and DAC for the treatment of common cancers, according to the researchers, because they are toxic to normal cells at standard high doses, and there was little research showing how they might work for cancer in general. Baylin and his colleague Cynthia Zahnow, Ph.D., decided to take another look at the drugs after low doses of the drugs showed a benefit in patients with a pre-leukemic disorder called myelodysplastic syndrome (MDS). Johns Hopkins investigators also showed benefit of low doses of the drugs in tests with a small number of advanced lung cancer patients. "This is contrary to the way we usually do things in cancer research," says Baylin, noting that "typically, we start in the laboratory and progress to clinical trials. In this case, we saw results in clinical trials that made us go back to the laboratory to figure out how to move the therapy forward."
For the research, Baylin and Zahnow's team worked with leukemia, breast, and other cancer cell lines and human tumor samples using the lowest possible doses that were effective against the cancers. In all, the investigators studied six leukemia cell lines, seven leukemia patient samples, three breast cancer cell lines, seven breast tumor samples (including four samples of tumors that had spread to the lung), one lung cancer tumor sample, and one colon cancer tumor sample. The team treated cell lines and tumor cells with low-dose AZA and DAC in culture for three days and allowed the drug-treated cells to rest for a week. Treated cells and tumor samples were then transplanted into mice where the researchers observed continued antitumor responses for up to 20 weeks. This extended response was in line with observations in some MDS patients who continued to have anticancer effects long after stopping the drug.
The low-dose therapy reversed cancer cell gene pathways, including those controlling cell cycle, cell repair, cell maturation, cell differentiation, immune cell interaction, and cell death. Effects varied among individual tumor cells, but the scientists generally saw that cancer cells reverted to a more normal state and eventually died. These results were caused, in part, by alteration of the epigenetic, or chemical environment, of DNA. Epigenetic activities turn on certain genes and block others, says Zahnow, assistant professor of oncology and the Evelyn Grolman Glick Scholar at Johns Hopkins.
The research team also tested AZA and DAC's effect on a type of metastatic breast cancer cell thought to drive cancer growth and resist standard therapies. Metastatic cells are difficult to study in standard laboratory tumor models, because they tend to break away from the original tumor and float around in blood and lymph fluids. The Johns Hopkins team re-created the metastatic stem cells' environment, allowing them to grow as floating spheres. "These cells were growing well as spheres in suspension, but when we treated the cells with AZA, both the size and number of spheres were dramatically reduced," says Zahnow.
The precise mechanism of how the drugs work is the focus of ongoing studies by Baylin and his team. "Our findings match evidence from recent clinical trials suggesting that the drugs shrink tumors more slowly over time as they repair altered mechanisms in cells and genes return to normal function and the cells may eventually die," says Baylin.
The results of clinical trials in lung cancer, led by Johns Hopkins' Charles Rudin, M.D., and published late last year in Cancer Discovery, also indicate that the drugs make tumors more responsive to standard anticancer drug treatment. This means, they say, that the drugs could become part of a combined treatment approach rather than a stand-alone therapy and as part of personalized approaches in patients whose cancers fit specific epigenetic and genetic profiles.
Low doses of both drugs are approved by the U.S. Food and Drug Administration for the treatment of MDS and chronic myelomonocytic leukemia (CMML). Clinical trials in breast and lung cancer have begun in patients with advanced disease, and trials in colon cancer are planned.
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