Women diagnosed with ductal carcinoma in situ (DCIS) need clear communication and tailored support to enable them to understand this complex breast condition, which has divided the medical profession when it comes to its perception and prognosis. That is the key finding of a study published in the April issue of the Journal of Advanced Nursing.
Research carried out at the University of the West of England, Bristol, UK, looked at how 45 women felt when they were diagnosed with DCIS and how their experiences changed over time. It found that many of the women were very confused about whether or not they had cancer and that medical staff often added to this confusion by providing conflicting messages.
“DCIS is a non-invasive condition where the cancer cells are contained in the ducts of the breast” explains lead author Dr Fiona Kennedy, now a research fellow at Sheffield Hallam University. “It currently makes up 20 per cent of breast cancers detected by UK screening programmes.
“However, uncertainty surrounds whether it will progress into invasive breast cancer and this has created two factions in the medical profession. Some view DCIS as a carcinoma in situ, emphasising that the majority of cases have a high risk of progression and need treatment to reduce the incidence of invasive breast cancer. Others view DCIS as a pre-cancerous condition.
“DCIS patients have an excellent prognosis, but treatment is controversial because it is similar to treatment for invasive breast cancer, including mastectomy and possibly radiotherapy and hormone treatment.
“This can be confusing for women diagnosed with DCIS. On the one hand they are being reassured that the condition is not life-threatening, yet on the other hand clinicians are recommending extensive, invasive treatment.”
The women, who were recruited from nine UK breast clinics, ranged from 34 to 84 years-of-age with an average age of 59. Seventy-six per cent had been diagnosed following screening and the rest had presented with symptoms. Some women had more than one surgical procedure, including wide local excision to remove the affected breast tissue (56%) or breast removal (44%).
Twenty-seven of the women took part in follow-up interviews nine to 13 months after diagnosis. All had completed their treatment and, during surgery, five had been diagnosed with DCIS in numerous sites (multifocal disease) or invasive breast cancer.
Key findings of the study, funded by the charity Breast Cancer Campaign, included:
Many women felt confused and conflicted by their diagnosis. Some were told it was cancer, some were told it wasn’t cancer and some medical staff used the terms DCIS, pre-cancer and early breast cancer. As one women said: “Sometimes they refer to it as breast cancer and then when I went to oncology last week they said it’s not breast cancer it’s pre-cancer…”Women spoke about the contradictions of being told it was pre-cancer or non- cancerous, their perceptions of what this meant and then being recommended extensive, invasive treatment. One woman’s surgeon said he didn’t know why she was so worried when she didn’t have cancer. “Well if I haven’t got cancer why am I having radiotherapy and why have you taken a 9cm by 6cm by 3cm chunk out of my breast?” she replied.Some women were more affected than others by their condition, especially if they had more extensive surgery. Many experienced mixed and fluctuating emotions. As one woman said: “At worst I feel mutilated and angry and upset…At best I feel relieved that it was nothing more.”One of the most enduring emotions was one of on-going risk, which ranged from fleeting concerns to significant, intrusive thoughts. They worried about DCIS reoccurring, or developing invasive breast cancer, and felt vulnerable and uncertain about the future.Body image was also a big issue and impacted on the women’s confidence and sexuality. “I felt that I wasn’t perfect in that area…I felt very exposed” said one woman. “I don’t know how I can go into a relationship and that makes me angry” said another after reconstructive surgery. Women who were confused about their own diagnosis found telling others very challenging. “I wanted them to know that there was a cancer in the title…you need to justify why you’re having such major surgery” said one. “If I said I’ve got breast cancer she [mum] would have been hysterical” said another, adding that she chose instead to describe is as “a really, really, really tiny area of pre-cancerous cells”.
“It was clear from our research that women’s perceptions and experiences of DCIS shifted and developed over time during the diagnosis, treatment and post-treatment phases” says Dr Kennedy. “Confusion about their medical condition was also very common as they received mixed messages about their diagnosis and whether it was or wasn’t cancer.
“One of the key recommendations of this study is that clinicians should think carefully about the language they use to describe DCIS and that further work is needed to explore the potential for the development of clear, coherent and flexible communication guidelines. There is also a need for appropriate and tailored help, support and information to meet the specific and evolving needs of women diagnosed with DCIS.”
Baroness Delyth Morgan, Chief Executive of the Breast Cancer Campaign, has welcomed the findings. “A diagnosis of DCIS can leave women confused about their treatment options as currently even clinicians don’t know which cases will progress to invasive breast cancer” she says. “For now we must give clearer messages to patients about what their diagnosis means and the potential risks to them if it is left untreated. Improving awareness of DCIS when women attend routine breast screening appointments is a key part of this process.”
Thursday, May 10, 2012
Monday, May 7, 2012
How a cancer drug leads to diabetes-like state
Scientists at Dana-Farber Cancer Institute have discovered why diabetic-like symptoms develop in some patients given rapamycin, an immune-suppressant drug that also has shown anti-cancer activity and may even slow aging.
Rapamycin is widely used to prevent organ rejection and is being tested as a cancer treatment in clinical trials. About 15 percent of patients, however, develop insulin resistance and glucose intolerance after taking the drug; until now, scientists had not identified the reason.
In a study published in Cell Metabolism, the researchers report that normal mice given rapamycin were more likely to have trouble regulating their blood sugar because of a drop in insulin signaling, which in turn was triggered by activity of a protein called Yin Yang 1, or YY1. But animals in which the YY1 protein was "knocked out" in their muscles had no such response to rapamycin -- they were protected against the development of diabetes-like symptoms. This result pinpointed YY1 as the target of rapamycin responsible for the loss of normal insulin function.
One of the finding's implications is that physicians should consider giving anti-diabetes drugs along with rapamycin, says Pere Puigserver, PhD, senior author of the report.
The results also raise a caution flag for researchers and non-scientists who are excited about the potential for rapamycin to extend life, based on recent studies in animals including mammals, he notes.
"The possibility of increased diabetes risk needs to be taken into account" in further research on the anti-aging properties of rapamycin and related compounds, says Puigserver.
Rapamycin is a drug derived from bacteria found on Easter Island, and was approved in 1999 by the FDA as an immunosuppressant in transplant patients.
One of its actions is to inhibit the important mTOR signaling pathway in cells (mTOR stands for "mammalian target of rapamycin"). The mTOR pathway is a critical factor in regulating the growth, proliferation, survival and motility of cells; elevated mTOR activity is a hallmark of many cancers.
In clinical trials rapamycin and a related drug are being evaluated in kidney cancer, brain tumors, and mantle cell lymphoma, among others. Intriguingly, rapamycin has been found in some experiments to extend healthy lifespan in yeast, flies and mammals, and delays age-related diseases, including cancer and atherosclerosis.
But the raised risk of deleterious pre-diabetes symptoms has been a concern and something of a mystery. In 2007, Puigserver and colleagues reported in Nature that mTOR causes an increase in mitochondria -- the cell's power plants -- in skeletal muscles; suppressing mTOR activity with rapamycin led to a diabetic state. That research also revealed that among the proteins "downstream" of mTOR in the signaling pathway is Yin Yang 1 (YY1), a transcription factor -- a protein that controls the expression of genes.
"We thought that maybe YY1 was responsible for the diabetic effects," says Puigserver. An increase in YY1 activity caused by rapamycin could suppress the production of insulin and related hormones which are necessary for muscles to take up glucose (sugar) for energy and keep blood sugar levels stable.
To test that idea, they bred mice that lacked the YYI gene and protein in their skeletal muscles. When these mice were given rapamycin, it didn't affect their muscles' glucose uptake or insulin signaling -- in effect, they were immune to the diabetic effects of rapamycin.
The investigators are continuing their studies: one goal is to discover why only a minority of human patients develop diabetes-like conditions with rapamycin treatment. One possibility that the risk is modulated by dietary factors, Puigserver says.
Rapamycin is widely used to prevent organ rejection and is being tested as a cancer treatment in clinical trials. About 15 percent of patients, however, develop insulin resistance and glucose intolerance after taking the drug; until now, scientists had not identified the reason.
In a study published in Cell Metabolism, the researchers report that normal mice given rapamycin were more likely to have trouble regulating their blood sugar because of a drop in insulin signaling, which in turn was triggered by activity of a protein called Yin Yang 1, or YY1. But animals in which the YY1 protein was "knocked out" in their muscles had no such response to rapamycin -- they were protected against the development of diabetes-like symptoms. This result pinpointed YY1 as the target of rapamycin responsible for the loss of normal insulin function.
One of the finding's implications is that physicians should consider giving anti-diabetes drugs along with rapamycin, says Pere Puigserver, PhD, senior author of the report.
The results also raise a caution flag for researchers and non-scientists who are excited about the potential for rapamycin to extend life, based on recent studies in animals including mammals, he notes.
"The possibility of increased diabetes risk needs to be taken into account" in further research on the anti-aging properties of rapamycin and related compounds, says Puigserver.
Rapamycin is a drug derived from bacteria found on Easter Island, and was approved in 1999 by the FDA as an immunosuppressant in transplant patients.
One of its actions is to inhibit the important mTOR signaling pathway in cells (mTOR stands for "mammalian target of rapamycin"). The mTOR pathway is a critical factor in regulating the growth, proliferation, survival and motility of cells; elevated mTOR activity is a hallmark of many cancers.
In clinical trials rapamycin and a related drug are being evaluated in kidney cancer, brain tumors, and mantle cell lymphoma, among others. Intriguingly, rapamycin has been found in some experiments to extend healthy lifespan in yeast, flies and mammals, and delays age-related diseases, including cancer and atherosclerosis.
But the raised risk of deleterious pre-diabetes symptoms has been a concern and something of a mystery. In 2007, Puigserver and colleagues reported in Nature that mTOR causes an increase in mitochondria -- the cell's power plants -- in skeletal muscles; suppressing mTOR activity with rapamycin led to a diabetic state. That research also revealed that among the proteins "downstream" of mTOR in the signaling pathway is Yin Yang 1 (YY1), a transcription factor -- a protein that controls the expression of genes.
"We thought that maybe YY1 was responsible for the diabetic effects," says Puigserver. An increase in YY1 activity caused by rapamycin could suppress the production of insulin and related hormones which are necessary for muscles to take up glucose (sugar) for energy and keep blood sugar levels stable.
To test that idea, they bred mice that lacked the YYI gene and protein in their skeletal muscles. When these mice were given rapamycin, it didn't affect their muscles' glucose uptake or insulin signaling -- in effect, they were immune to the diabetic effects of rapamycin.
The investigators are continuing their studies: one goal is to discover why only a minority of human patients develop diabetes-like conditions with rapamycin treatment. One possibility that the risk is modulated by dietary factors, Puigserver says.
Sunday, May 6, 2012
New clues to development of blood and other cancers
Scientists at Fox Chase Cancer Center have uncovered more details about how defects in components of the machinery that makes new proteins can lead to blood and other cancers. The findings may one day lead to new targeted therapies that address those problems.
"These findings help explain how mutations in one class of proteins can trigger the development of cancer," says Shuyun Rao, PhD, a scientific associate in the lab of David L. Wiest, PhD, also a co-author on the study, at Fox Chase Cancer Center in Philadelphia. "If we find a way to block the pathway activated by these mutations, this may cause tumors to regress."
The research focused specifically on ribosomal proteins. Previous research has linked mutations in ribosomal proteins to cancers such as leukemia and lymphoma, as well as myelodysplastic syndromes (MDS), which can lead to acute myelogenous leukemia (AML). However, this study represents the first insights into how mutations in ribosomal proteins might increase cancer risk.
To investigate further how an individual ribosomal protein might trigger cancer, Rao, Wiest and their colleagues focused on one known as L22. To begin, they looked at blood samples from a small number of leukemia patients -- approximately 50 -- and found that in 9%, L22 was either mutated or deleted entirely. This suggested that problems in L22 may have played a role in the development of their cancers.
Next, they deleted L22 in mice that were bred to be prone to develop lymphomas, and saw that their tumors developed faster, and the mice died faster than those who had intact forms of L22 -- further evidence of its important role in the disease.
Finally, in a sample of cells in the lab, the researchers inactivated L22 and saw that the cells experienced changes, signaling the early stages of lymphoma. Specifically, cells without L22 showed more activity in a pathway associated with inflammation known as NFkappaB, which other research has linked to cancer. "In theory, if we could find a way to block this pathway, we could add this to existing therapies to help treat the tumors it triggers," says Rao.
Although L22 is a ribosomal protein, and therefore helps build new proteins, previous research has found that eliminating L22 does not affect the rate with which cells make new proteins -- suggesting L22 has additional functions, says Rao.
Previous research has found that L22 expression is strikingly reduced in a number of liquid and solid tumors including breast cancer, lung adenocarcinoma and ovarian carcinoma. "These findings don't just have implications for people with leukemia," Wiest says. "It is likely that L22 repression or inactivation will play a role in other cancer types as well"
Co-authors on the study include researchers at Fox Chase, Dana-Farber Cancer Institute in Boston, Massachusetts; St. Jude Children's Research Hospital in Memphis, Tennessee; and the University of Colorado Denver School of Medicine in Aurora, Colorado.
"These findings help explain how mutations in one class of proteins can trigger the development of cancer," says Shuyun Rao, PhD, a scientific associate in the lab of David L. Wiest, PhD, also a co-author on the study, at Fox Chase Cancer Center in Philadelphia. "If we find a way to block the pathway activated by these mutations, this may cause tumors to regress."
The research focused specifically on ribosomal proteins. Previous research has linked mutations in ribosomal proteins to cancers such as leukemia and lymphoma, as well as myelodysplastic syndromes (MDS), which can lead to acute myelogenous leukemia (AML). However, this study represents the first insights into how mutations in ribosomal proteins might increase cancer risk.
To investigate further how an individual ribosomal protein might trigger cancer, Rao, Wiest and their colleagues focused on one known as L22. To begin, they looked at blood samples from a small number of leukemia patients -- approximately 50 -- and found that in 9%, L22 was either mutated or deleted entirely. This suggested that problems in L22 may have played a role in the development of their cancers.
Next, they deleted L22 in mice that were bred to be prone to develop lymphomas, and saw that their tumors developed faster, and the mice died faster than those who had intact forms of L22 -- further evidence of its important role in the disease.
Finally, in a sample of cells in the lab, the researchers inactivated L22 and saw that the cells experienced changes, signaling the early stages of lymphoma. Specifically, cells without L22 showed more activity in a pathway associated with inflammation known as NFkappaB, which other research has linked to cancer. "In theory, if we could find a way to block this pathway, we could add this to existing therapies to help treat the tumors it triggers," says Rao.
Although L22 is a ribosomal protein, and therefore helps build new proteins, previous research has found that eliminating L22 does not affect the rate with which cells make new proteins -- suggesting L22 has additional functions, says Rao.
Previous research has found that L22 expression is strikingly reduced in a number of liquid and solid tumors including breast cancer, lung adenocarcinoma and ovarian carcinoma. "These findings don't just have implications for people with leukemia," Wiest says. "It is likely that L22 repression or inactivation will play a role in other cancer types as well"
Co-authors on the study include researchers at Fox Chase, Dana-Farber Cancer Institute in Boston, Massachusetts; St. Jude Children's Research Hospital in Memphis, Tennessee; and the University of Colorado Denver School of Medicine in Aurora, Colorado.
Breast cancer survival may improve by eating cruciferous vegetables
A study by Vanderbilt-Ingram Cancer Center and Shanghai Center for Disease Control and Prevention investigators reveals that breast cancer survivors who eat more cruciferous vegetables may have improved survival. The study of women in China was presented by postdoctoral fellow Sarah J. Nechuta, Ph.D., M.P.H., at the American Association for Cancer Research Annual Meeting in Chicago, Ill.
"Breast cancer survivors can follow the general nutritional guidelines of eating vegetables daily and may consider increasing intake of cruciferous vegetables, such as greens, cabbage, cauliflower and broccoli, as part of a healthy diet," said Nechuta.
Nechuta, Xiao Ou Shu, M.D., Ph.D., and colleagues investigated the role of cruciferous vegetables in breast cancer survival among women in the Shanghai Breast Cancer Survival Study, a prospective study of 4,886 Chinese breast cancer survivors who were diagnosed with stage 1 to stage 4 breast cancer from 2002 to 2006. Shu, Ingram Professor of Cancer Research, is the principal investigator of the Shanghai Breast Cancer Survival Study.
After adjusting for demographics, clinical characteristics and lifestyle factors, the researchers found cruciferous vegetable intake during the first 36 months after breast cancer diagnosis was associated with a reduced risk for total mortality, breast cancer-specific mortality and disease recurrence.
Survival rates were influenced by vegetable consumption in a dose-response pattern. As women ate more of these vegetables, their risk of death or cancer recurrence decreased.
Women who were in the highest quartiles of intake of vegetables per day had a 62 percent reduced risk of total mortality, 62 percent reduced risk of breast cancer mortality, and 35 percent reduced risk of breast cancer recurrence, compared to women with the lowest quartile of intake."
Nechuta noted that cruciferous vegetable consumption habits differ between China and the United States and suggested this fact be considered when generalizing these results to U.S. breast cancer survivors.
"Commonly consumed cruciferous vegetables in China include turnips, Chinese cabbage/bok choy and greens, while broccoli and Brussels sprouts are the more commonly consumed cruciferous vegetables in the United States and other Western countries," she said. "The amount of intake among Chinese women is also much higher than that of U.S. women."
Cruciferous vegetables contain phytochemicals known as isothiocyanates and indoles which appear to have a protective effect against some types of cancer.
Nechuta said the level of these bioactive compounds, proposed to play a role in the anticancer effects of cruciferous vegetables, depends on both the amount and type of cruciferous vegetables consumed.
She said there is a need for future studies that measure the bioactive compounds in these vegetables and the host factors that may influence the effects of these compounds to improve the understanding of the association between cruciferous vegetable consumption and breast cancer outcomes.
"Breast cancer survivors can follow the general nutritional guidelines of eating vegetables daily and may consider increasing intake of cruciferous vegetables, such as greens, cabbage, cauliflower and broccoli, as part of a healthy diet," said Nechuta.
Nechuta, Xiao Ou Shu, M.D., Ph.D., and colleagues investigated the role of cruciferous vegetables in breast cancer survival among women in the Shanghai Breast Cancer Survival Study, a prospective study of 4,886 Chinese breast cancer survivors who were diagnosed with stage 1 to stage 4 breast cancer from 2002 to 2006. Shu, Ingram Professor of Cancer Research, is the principal investigator of the Shanghai Breast Cancer Survival Study.
After adjusting for demographics, clinical characteristics and lifestyle factors, the researchers found cruciferous vegetable intake during the first 36 months after breast cancer diagnosis was associated with a reduced risk for total mortality, breast cancer-specific mortality and disease recurrence.
Survival rates were influenced by vegetable consumption in a dose-response pattern. As women ate more of these vegetables, their risk of death or cancer recurrence decreased.
Women who were in the highest quartiles of intake of vegetables per day had a 62 percent reduced risk of total mortality, 62 percent reduced risk of breast cancer mortality, and 35 percent reduced risk of breast cancer recurrence, compared to women with the lowest quartile of intake."
Nechuta noted that cruciferous vegetable consumption habits differ between China and the United States and suggested this fact be considered when generalizing these results to U.S. breast cancer survivors.
"Commonly consumed cruciferous vegetables in China include turnips, Chinese cabbage/bok choy and greens, while broccoli and Brussels sprouts are the more commonly consumed cruciferous vegetables in the United States and other Western countries," she said. "The amount of intake among Chinese women is also much higher than that of U.S. women."
Cruciferous vegetables contain phytochemicals known as isothiocyanates and indoles which appear to have a protective effect against some types of cancer.
Nechuta said the level of these bioactive compounds, proposed to play a role in the anticancer effects of cruciferous vegetables, depends on both the amount and type of cruciferous vegetables consumed.
She said there is a need for future studies that measure the bioactive compounds in these vegetables and the host factors that may influence the effects of these compounds to improve the understanding of the association between cruciferous vegetable consumption and breast cancer outcomes.
Saturday, May 5, 2012
Scientists discovered how cancers override cellular growth controls
Rapidly dividing cancer cells are skilled at patching up damage that would stop normal cells in their tracks, including wear and tear of telomeres, the protective caps at the end of each chromosome.
Loss of telomeres forces cells out of the dividing game and into a growth arrest state called "senescence," but cancer cells evade this by employing an enzyme called telomerase to extend eroded telomeres.
If telomerase fails to activate, the tumor cells of about 10 percent of all human cancers have a back-up strategy to build serviceable telomeres and keep dividing. How that pathway, called ALT for alternative lengthening of telomeres, works is unclear, because researchers have had limited options to study it experimentally.
Now scientists at the at Salk Institute for Biological Studies have created roundworms that eke out an existence, and even manage to reproduce, relying solely on ALT to maintain telomeres. That study provides a valuable tool to tinker with the ALT pathway and learn how to block it, with a goal of forcing tumor cells to senesce.
"These worms are the first multicellular organisms we can study in the laboratory that maintain their telomeres through the ALT pathway and not through telomerase," says Jan Karlseder, a professor in Salk's Molecular and Cell Biology Laboratory and the study's senior author. "Up to now we could only study ALT in cell lines derived from tumor cells. Now we can screen for compounds and genes that suppress or regulate ALT in a whole organism, which in worms is fairly easy to do."
The components of telomere-building pathways are prime targets for cancer researchers. "There is a huge interest in drugs that block telomerase, since 90 percent of cancers use it for telomere maintenance," says Daniel Lackner, a postdoctoral fellow in the Karlseder lab and one of the study's first authors. "But these drugs won't work for the 10 percent of cancers that use the ALT pathway. In fact, some evidence suggests that drugs targeting telomerase might actually increase ALT, making the need for ALT inhibitors more pressing."
In contrast, the bottom rows show abnormally fused chromosomes found in genetically altered roundworms created by the Salk researchers.
Despite this irregularity, the Salk researchers' worms were able to reproduce, providing a new avenue for scientists to study a key pathway in the development of certain cancers.
The new study stems from a 2008 study from the Karlseder lab that was published in Cell. In that paper, they mutated a gene encoding a telomere-binding protein in roundworms. The resulting mutants displayed functional, but slightly scruffier-looking telomeres than those built by telomerase. That was a strong hint that when forced, worm cells, like human cells, can turn on the ALT pathway.
For the new study, the team pushed the mutant worms' survival capacity to the limit. This time they knocked out a second gene, telomerase itself, and found that these double mutants could reproduce continuously without undergoing senescence. Over the past 3 years a strain of double mutant worms has propagated for over 180 generations.
The group then used biochemistry to confirm that the worms depend totally on ALT for telomere maintenance. The telomeres of double mutants were more sloppily constructed than superior, telomerase-made caps and were similar in length and overall structure to chromosome caps displayed by human cancer cells that employ ALT.
The double mutant worms also contained wisps of telomeric DNA, called c-circles, that are unique by-products of ALT, further evidence that they were persisting via ALT.
Intriguingly, other investigators have reported that c-circles are present in the blood of human bone cancer patients and could potentially serve as a diagnostic for cancers that depend on the ALT rather than the telomerase pathway.
Although the worms are living long, species-wise, they are not quite prospering -- which is exactly what one would expect. The study reports that the double mutants have fewer offspring than normal worms, which is how roundworms exhibit "stress." And many have fused chromosomes, a likely outcome of having barely serviceable telomeres. But what counts is that the animals are viable, rely on ALT only, and their genome reflects aberrations seen in human tumor cells. In short, they are ready for analysis.
Currently, researchers cannot predict what mechanisms a cancer will to use to maintain the telomeres. "Cancers of the bones, stomach and soft tissues may be more efficient in activating ALT than telomerase pathways," says Karlseder, noting that indicators of ALT have also been observed in other cancer types. "We don't know why a tumor chooses one pathway over the other. All we know is that ALT may be switched on in response to telomerase inhibition, which means we must understand this pathway."
Marcela Raices, a former Salk postdoctoral fellow, now at University of California San Francisco, was co-first author with Lackner on the paper. Also contributing were Candy Haggblom of the Karlseder lab and Hugo Maruyama, a former graduate student in the lab, now at Osaka Dental University.
Loss of telomeres forces cells out of the dividing game and into a growth arrest state called "senescence," but cancer cells evade this by employing an enzyme called telomerase to extend eroded telomeres.
If telomerase fails to activate, the tumor cells of about 10 percent of all human cancers have a back-up strategy to build serviceable telomeres and keep dividing. How that pathway, called ALT for alternative lengthening of telomeres, works is unclear, because researchers have had limited options to study it experimentally.
Now scientists at the at Salk Institute for Biological Studies have created roundworms that eke out an existence, and even manage to reproduce, relying solely on ALT to maintain telomeres. That study provides a valuable tool to tinker with the ALT pathway and learn how to block it, with a goal of forcing tumor cells to senesce.
"These worms are the first multicellular organisms we can study in the laboratory that maintain their telomeres through the ALT pathway and not through telomerase," says Jan Karlseder, a professor in Salk's Molecular and Cell Biology Laboratory and the study's senior author. "Up to now we could only study ALT in cell lines derived from tumor cells. Now we can screen for compounds and genes that suppress or regulate ALT in a whole organism, which in worms is fairly easy to do."
The components of telomere-building pathways are prime targets for cancer researchers. "There is a huge interest in drugs that block telomerase, since 90 percent of cancers use it for telomere maintenance," says Daniel Lackner, a postdoctoral fellow in the Karlseder lab and one of the study's first authors. "But these drugs won't work for the 10 percent of cancers that use the ALT pathway. In fact, some evidence suggests that drugs targeting telomerase might actually increase ALT, making the need for ALT inhibitors more pressing."
In contrast, the bottom rows show abnormally fused chromosomes found in genetically altered roundworms created by the Salk researchers.
Despite this irregularity, the Salk researchers' worms were able to reproduce, providing a new avenue for scientists to study a key pathway in the development of certain cancers.
The new study stems from a 2008 study from the Karlseder lab that was published in Cell. In that paper, they mutated a gene encoding a telomere-binding protein in roundworms. The resulting mutants displayed functional, but slightly scruffier-looking telomeres than those built by telomerase. That was a strong hint that when forced, worm cells, like human cells, can turn on the ALT pathway.
For the new study, the team pushed the mutant worms' survival capacity to the limit. This time they knocked out a second gene, telomerase itself, and found that these double mutants could reproduce continuously without undergoing senescence. Over the past 3 years a strain of double mutant worms has propagated for over 180 generations.
The group then used biochemistry to confirm that the worms depend totally on ALT for telomere maintenance. The telomeres of double mutants were more sloppily constructed than superior, telomerase-made caps and were similar in length and overall structure to chromosome caps displayed by human cancer cells that employ ALT.
The double mutant worms also contained wisps of telomeric DNA, called c-circles, that are unique by-products of ALT, further evidence that they were persisting via ALT.
Intriguingly, other investigators have reported that c-circles are present in the blood of human bone cancer patients and could potentially serve as a diagnostic for cancers that depend on the ALT rather than the telomerase pathway.
Although the worms are living long, species-wise, they are not quite prospering -- which is exactly what one would expect. The study reports that the double mutants have fewer offspring than normal worms, which is how roundworms exhibit "stress." And many have fused chromosomes, a likely outcome of having barely serviceable telomeres. But what counts is that the animals are viable, rely on ALT only, and their genome reflects aberrations seen in human tumor cells. In short, they are ready for analysis.
Currently, researchers cannot predict what mechanisms a cancer will to use to maintain the telomeres. "Cancers of the bones, stomach and soft tissues may be more efficient in activating ALT than telomerase pathways," says Karlseder, noting that indicators of ALT have also been observed in other cancer types. "We don't know why a tumor chooses one pathway over the other. All we know is that ALT may be switched on in response to telomerase inhibition, which means we must understand this pathway."
Marcela Raices, a former Salk postdoctoral fellow, now at University of California San Francisco, was co-first author with Lackner on the paper. Also contributing were Candy Haggblom of the Karlseder lab and Hugo Maruyama, a former graduate student in the lab, now at Osaka Dental University.
Friday, May 4, 2012
Human virus to treat head and neck cancer patients
A naturally-occurring harmless human virus may be able to boost the effects of two standard chemotherapy drugs in some cancer patients, according to early stage trial data published April 1 in Clinical Cancer Research. Cancers shrank for about one third of the patients who could be evaluated, and disease stabilized for a further third. For one patient, all signs of their cancer disappeared.
RT3D, trade name Reolysin, is a new drug developed by Oncolytics Biotech Inc with preclinical and clinical studies conducted at The Institute of Cancer Research (ICR) and The Royal Marsden Hospital. It is based on a virus (reovirus type 3 Dearing) that is found in almost all adults' respiratory and gastrointestinal tracts without causing any symptoms.
RT3D has the ability to grow in and kill certain types of cancer cells, but does not grow in normal cells.
Previous trials injecting patients with the virus on its own showed limited effectiveness, but the team found that RT3D appeared to magnify the effects of platin and taxane-based chemotherapy on tumour cells.
Dr Kevin Harrington and colleagues in Leeds therefore started a clinical trial testing intravenous RT3D in combination with chemotherapeutics carboplatin and paclitaxel in 31 patients with advanced cancers who had stopped responding to standard treatments.
An initial Phase I study was carried out in patients with a range of advanced cancers, which showed the drug combination was safe. Side-effects were found to be generally mild, and consistent with chemotherapy alone.
Patients with head and neck cancers were found to have the best responses, so a Phase II expansion study at The Royal Marsden Hospital, London, and St James's Hospital, Leeds, was therefore targeted to patients with these types of cancers.
Cancers shrank for about one third of the patients who could be evaluated, and disease stabilised for a further third. For one patient, all signs of their cancer disappeared.
"We saw really very impressive response rates in these patients. These are patients whose cancers had grown despite a great deal of previous treatment, including platinum-based chemotherapy for many," Dr Harrington, Leader of the ICR's Targeted Therapy Team and Consultant Oncologist at The Royal Marsden, said. "Under those circumstances, we'd expect that the average response rate to chemotherapy alone might be as low as single digits figures and the average survival would be somewhere between three to four months. In our Phase I/II study we show this had been prolonged to an average of seven months, albeit not in a randomised trial."
"Based on the results of this study we've now started recruiting patients with advanced head and neck cancer to a randomised Phase III trial, in which all patients will receive chemotherapy and half will receive Reolysin as well. We are extremely excited about this progress."
The study also found the virus was not shed after treatment. This means people could be given the drug as outpatients as no risk was found that they could transmit the virus to others.
Head and neck cancers include tumours of the eye, nasal cavity, tongue, gums, lip, cheeks, voice box and esophagus. Around 650,000 people are diagnosed with squamous cell cancer of the head and neck each year worldwide, and around 350,000 die from the disease annually.
Notes to editors: Phase I/II trial of carboplatin and paclitaxel chemotherapy in combination with intravenous oncolytic reovirus in patients with advanced malignancies with first author Eleni M. Karapanagiotou from the ICR and The Royal Marsden publishes in the print edition of Clinical Cancer Research on April 1.
The Phase III trial is recruiting patients with head and neck cancer who have already been treated with platinum but not taxane.
RT3D, trade name Reolysin, is a new drug developed by Oncolytics Biotech Inc with preclinical and clinical studies conducted at The Institute of Cancer Research (ICR) and The Royal Marsden Hospital. It is based on a virus (reovirus type 3 Dearing) that is found in almost all adults' respiratory and gastrointestinal tracts without causing any symptoms.
RT3D has the ability to grow in and kill certain types of cancer cells, but does not grow in normal cells.
Previous trials injecting patients with the virus on its own showed limited effectiveness, but the team found that RT3D appeared to magnify the effects of platin and taxane-based chemotherapy on tumour cells.
Dr Kevin Harrington and colleagues in Leeds therefore started a clinical trial testing intravenous RT3D in combination with chemotherapeutics carboplatin and paclitaxel in 31 patients with advanced cancers who had stopped responding to standard treatments.
An initial Phase I study was carried out in patients with a range of advanced cancers, which showed the drug combination was safe. Side-effects were found to be generally mild, and consistent with chemotherapy alone.
Patients with head and neck cancers were found to have the best responses, so a Phase II expansion study at The Royal Marsden Hospital, London, and St James's Hospital, Leeds, was therefore targeted to patients with these types of cancers.
Cancers shrank for about one third of the patients who could be evaluated, and disease stabilised for a further third. For one patient, all signs of their cancer disappeared.
"We saw really very impressive response rates in these patients. These are patients whose cancers had grown despite a great deal of previous treatment, including platinum-based chemotherapy for many," Dr Harrington, Leader of the ICR's Targeted Therapy Team and Consultant Oncologist at The Royal Marsden, said. "Under those circumstances, we'd expect that the average response rate to chemotherapy alone might be as low as single digits figures and the average survival would be somewhere between three to four months. In our Phase I/II study we show this had been prolonged to an average of seven months, albeit not in a randomised trial."
"Based on the results of this study we've now started recruiting patients with advanced head and neck cancer to a randomised Phase III trial, in which all patients will receive chemotherapy and half will receive Reolysin as well. We are extremely excited about this progress."
The study also found the virus was not shed after treatment. This means people could be given the drug as outpatients as no risk was found that they could transmit the virus to others.
Head and neck cancers include tumours of the eye, nasal cavity, tongue, gums, lip, cheeks, voice box and esophagus. Around 650,000 people are diagnosed with squamous cell cancer of the head and neck each year worldwide, and around 350,000 die from the disease annually.
Notes to editors: Phase I/II trial of carboplatin and paclitaxel chemotherapy in combination with intravenous oncolytic reovirus in patients with advanced malignancies with first author Eleni M. Karapanagiotou from the ICR and The Royal Marsden publishes in the print edition of Clinical Cancer Research on April 1.
The Phase III trial is recruiting patients with head and neck cancer who have already been treated with platinum but not taxane.
Thursday, May 3, 2012
Research gives hope to detecting cancer in early stages
Research from Queen Mary, University of London has uncovered the mechanism which causes normal cells to develop into cancer, giving hope in the fight against one of the UK's biggest killers.
The study, published in the online journal PLoS ONE on March 26, investigated the role of the notorious cancer gene FOXM1.
Lead investigator Dr Muy-Teck Teh from Queen Mary, University of London, said the team found that the FOXM1 gene "brain washes" normal cells so they adopt a 'memory' pattern similar to cancer cells.
"This research has important clinical implications for early cancer diagnosis, prevention and treatment.
"We knew the FOXM1 gene is present in almost all different types of human cancers so we wanted to understand how excessive levels of it cause normal cells to become cancer-like."
Dr Teh's team used a gene-chip microarray technology to investigate the DNA 'memory' patterns in cells.
Normal cells inherit specific instructions or 'memory' patterns by masking and unmasking parts of their DNA. Maintaining the correct memory patterns is important for normal cell function -- disturbing the memory pattern can lead to cancer formation.
"We knew that excess expression of FOXM1 can lead to cancer but its underlying mechanism was not clear," Dr Teh explained.
"We looked at normal human mouth cells and introduced high levels of FOXM1. The normal cells changed to adopt a memory pattern similar to those in mouth cancer cells and we identified a number of key pattern changes that may be responsible for initiating cancer formation.
"These pattern changes may lead to the identification of biomarkers which could be developed into new diagnostic tests. We are currently working towards developing a practical diagnostic test for detecting mouth cancer at very early stages."
The team's research, funded by the Wellcome Trust and the Facial Surgery Research Foundation, Saving Faces, means that it will be easier to detect changes in cells before they develop into cancer.
Consultant oral and maxillofacial surgeon Professor Iain Hutchison, founder of Saving Faces and co-author on the study, said: "We are excited about this finding as it means that we can now detect changes in cells way before they become cancer cells.
"Mouth cancer, if detected early when the disease is most receptive to surgical treatment, has a very high cure rate. Understanding how a gene such as FOXM1 can convert normal cells into cancer is an important step towards finding new diagnostic tests for early cancer detection."
This study builds on previous studies Dr Teh and his team has done on FOXM1. Published in 2009, Dr Teh found that nicotine could activate FOXM1 and that excessive levels could cause normal human mouth cells to develop into cancer. His research on FOXM1 was awarded 'Molecule of the Year 2010' by the International Society for Molecular and Cell Biology and Biotechnology Protocols and Research for its pivotal role in cancer stem-cell biology.
The study, published in the online journal PLoS ONE on March 26, investigated the role of the notorious cancer gene FOXM1.
Lead investigator Dr Muy-Teck Teh from Queen Mary, University of London, said the team found that the FOXM1 gene "brain washes" normal cells so they adopt a 'memory' pattern similar to cancer cells.
"This research has important clinical implications for early cancer diagnosis, prevention and treatment.
"We knew the FOXM1 gene is present in almost all different types of human cancers so we wanted to understand how excessive levels of it cause normal cells to become cancer-like."
Dr Teh's team used a gene-chip microarray technology to investigate the DNA 'memory' patterns in cells.
Normal cells inherit specific instructions or 'memory' patterns by masking and unmasking parts of their DNA. Maintaining the correct memory patterns is important for normal cell function -- disturbing the memory pattern can lead to cancer formation.
"We knew that excess expression of FOXM1 can lead to cancer but its underlying mechanism was not clear," Dr Teh explained.
"We looked at normal human mouth cells and introduced high levels of FOXM1. The normal cells changed to adopt a memory pattern similar to those in mouth cancer cells and we identified a number of key pattern changes that may be responsible for initiating cancer formation.
"These pattern changes may lead to the identification of biomarkers which could be developed into new diagnostic tests. We are currently working towards developing a practical diagnostic test for detecting mouth cancer at very early stages."
The team's research, funded by the Wellcome Trust and the Facial Surgery Research Foundation, Saving Faces, means that it will be easier to detect changes in cells before they develop into cancer.
Consultant oral and maxillofacial surgeon Professor Iain Hutchison, founder of Saving Faces and co-author on the study, said: "We are excited about this finding as it means that we can now detect changes in cells way before they become cancer cells.
"Mouth cancer, if detected early when the disease is most receptive to surgical treatment, has a very high cure rate. Understanding how a gene such as FOXM1 can convert normal cells into cancer is an important step towards finding new diagnostic tests for early cancer detection."
This study builds on previous studies Dr Teh and his team has done on FOXM1. Published in 2009, Dr Teh found that nicotine could activate FOXM1 and that excessive levels could cause normal human mouth cells to develop into cancer. His research on FOXM1 was awarded 'Molecule of the Year 2010' by the International Society for Molecular and Cell Biology and Biotechnology Protocols and Research for its pivotal role in cancer stem-cell biology.
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