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Improving efficacy of drugs would boost post-surgery survivorship
Researchers at the UC Davis Cancer Center have discovered a way of sensitizing muscle-invasive bladder cancer cells so that they succumb to the toxic effects of chemotherapy. The finding adds to mounting evidence that tiny strands of RNA — called microRNA — play key roles in some of the deadliest types of cancer.
In the current study, published online June 28 in International Journal of Cancer, researchers boosted the production of a microRNA found in bladder cancer cell lines — encoded for by the gene miR-34a — and found that this resulted in more of the cells being killed by cisplatin, a chemotherapy drug used to treat many types of cancer.
Ralph deVere White
"When we took the bladder cancer cell lines and activated miR-34a, they were more responsive to chemotherapy," said Ralph deVere White, UC Davis Cancer Center director and professor of urology.
The study establishes, for the first time, a link between sensitivity of bladder cancer cells to chemotherapy and the expression of miR-34a. It suggests that miR-34a may be used as a predictor of response to chemotherapy, as well as a target for new drugs.
Currently, about 50 percent of patients with advanced bladder cancer will survive five years after diagnosis. Although clinical trials have demonstrated that chemotherapy before surgery can improve survival rates, it is rarely used because fewer than 50 percent of patients will respond favorably. Without knowing which patients will improve as a result of chemotherapy, physicians are generally reluctant to use a treatment that can cause their patients to suffer significant side effects.
"So, now we have to prove that it works to predict chemotherapy response in patients," deVere White said. To that end, UC Davis has entered into a partnership with Israel-based Rosetta Genomics to develop a microRNA profile for muscle-invasive bladder cancer that may be used to predict response to chemotherapy.
As part of the current study, deVere White and his colleagues studied 27 patients and found that many who expressed lower levels of miR-34a subsequently did not respond to the combined chemotherapy-surgery treatment. Because the finding was not statistically significant, however, further work in this area is needed.
The team also studied tumor samples taken from eight of the patients who did not respond to chemotherapy. They compared the expression of miR-34a before and after chemotherapy.
"We wanted to see, if you looked at the patient's tissue before chemotherapy, were there differentially expressed microRNAs in the patients who responded to the drugs versus those that didn't respond," deVere White explained.
The team found that expression of miR-34a increased after treatment in only two of the eight cases, suggesting that gene expression levels remained low during treatment and confirming the link between low gene expression and failure to respond to treatment.
"The combined data indicate that the elevation of miR-34a expression levels prior to chemotherapy would be of benefit to muscle-invasive bladder cancer patients, particularly in a setting of low mi-R-34a expression," the authors write.
Since their discovery in 1993, microRNAs have been found to be involved in a number of types of cancer, heart disease and diseases of the nervous system. In 2007, deVere White was part of a team that identified miR-125b, a gene that encodes for a microRNA that jump starts prostate cancer cell growth midway through the disease process, eventually causing it to become fatal.
The microRNA studied here was also recently found to play a role in medulloblastoma, an aggressive type of brain cancer. MicroRNAs, which are usually 22 to 33 nucleotides in length, are known as post-transcriptional regulators. That means they work by turning genes on or off during the part of the protein synthesis process that involves making a strand of RNA from a DNA template. The human genome encodes for an estimated 1,000 microRNAs.
According to the authors, future studies involving miR-34a will focus on testing its ability to increase sensitivity to chemotherapy and analysis of miR-34a expression in patients with muscle-invasive bladder cancer. With the currently low chemotherapy success rate and poor five-year survival rate for patients with this disease, "such studies are clearly warranted," the authors write.
"If we can prove what is causing chemotherapy resistance in patients with muscle-invasive bladder cancer, American ingenuity will come up with ways to overcome it," predicted deVere White.
Wednesday, June 29, 2011
Friday, June 24, 2011
Smokers With Prostate Cancer Have Higher Death Risk
A just-released study about smoking and prostate cancer gives men one more reason to quit. The study says that smokers who are diagnosed with prostate cancer may have an increased risk of dying from the disease compared to non-smokers. They also have an increased risk of the cancer coming back.
Researchers from the Harvard School of Public Health, Boston studied 5,366 men diagnosed with prostate cancer between 1986 and 2006. Five years after diagnosis, 94.8% of men who had never smoked had not died of their prostate cancer, compared with 91.7% of current smokers.
The study, called "Smoking and Prostate Cancer Survival and Recurrence, is published in the June 22/29 issue of the Journal of the American Medical Association.
Durado D. Brooks, MD, American Cancer Society director of prostate and colorectal cancer, says this study is significant because it’s the largest study of its kind to show links between smoking and the likelihood of dying from prostate cancer.
It also takes into account several factors associated with negative outcomes of prostate cancer, including Gleason score (a measure of how likely the cancer is to grow quickly) and the stage of cancer at diagnosis. Previous studies have shown a link between smoking and being diagnosed at a later stage, and the new study accounted for that.
Brooks says this suggests something about cigarettes themselves, and not just the men’s behavior, is causing the increased risk of prostate cancer death.
The study also showed that men who had quit smoking at least 10 years before their diagnosis had prostate cancer death risks similar to men who had never smoked. Brooks says this means it’s never too late to quit. "Never smoke. Don’t start. If you smoke, quit now. It’s never too late."
Researchers from the Harvard School of Public Health, Boston studied 5,366 men diagnosed with prostate cancer between 1986 and 2006. Five years after diagnosis, 94.8% of men who had never smoked had not died of their prostate cancer, compared with 91.7% of current smokers.
The study, called "Smoking and Prostate Cancer Survival and Recurrence, is published in the June 22/29 issue of the Journal of the American Medical Association.
Durado D. Brooks, MD, American Cancer Society director of prostate and colorectal cancer, says this study is significant because it’s the largest study of its kind to show links between smoking and the likelihood of dying from prostate cancer.
It also takes into account several factors associated with negative outcomes of prostate cancer, including Gleason score (a measure of how likely the cancer is to grow quickly) and the stage of cancer at diagnosis. Previous studies have shown a link between smoking and being diagnosed at a later stage, and the new study accounted for that.
Brooks says this suggests something about cigarettes themselves, and not just the men’s behavior, is causing the increased risk of prostate cancer death.
The study also showed that men who had quit smoking at least 10 years before their diagnosis had prostate cancer death risks similar to men who had never smoked. Brooks says this means it’s never too late to quit. "Never smoke. Don’t start. If you smoke, quit now. It’s never too late."
Saturday, June 4, 2011
Study links acetaminophen to lower prostate cancer risk
A new study from American Cancer Society researchers finds use of 30 tablets a month or more of acetaminophen (Anacin)for five or more years was associated with an estimated 38% lower risk of prostate cancer. The study appears in Cancer Epidemiology, Biomarkers and Prevention and is one of only two studies of prostate cancer to date that have examined the association with acetaminophen use that was both long-term and regular.
Use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), particularly long-term use, has been associated with modestly reduced risk of prostate cancer in some previous epidemiologic studies. Acetaminophen, a commonly used pain-reliever, is not traditionally considered an NSAID but can have anti-inflammatory effects.
For the current study, researchers led by Eric Jacobs, Ph.D., American Cancer Society epidemiologist, examined the association between acetaminophen use and prostate cancer incidence among 78,485 men in the Cancer Prevention Study II Nutrition Cohort. Information on acetaminophen use was obtained from a questionnaire completed at study enrollment in 1992 and updated using follow-up questionnaires in 1997 and every two years thereafter.
During follow-up from 1992 through 2007, there were 8,092 incident prostate cancer cases identified. Current regular use of acetaminophen (> 30 pills per month) for 5 years or more was associated with lower risk of overall prostate cancer (RR = 0.62, 95% CI 0.44-0.87) as well as lower risk of aggressive prostate cancer (RR = 0.49, 95% CI 0.27-0.88). Current regular use of < 5 years duration was not associated with prostate cancer risk.
"While the results of this observational study suggest that long-term regular acetaminophen use may be associated with lower prostate cancer risk, our findings require replication by other studies, and do not justify use of acetaminophen to prevent prostate cancer. Acetaminophen is considered relatively safe when used at recommended doses but unintentional acetaminophen overdose is an important cause of acute liver failure." said Dr. Jacobs. "Still, results of this study could lead to further research on acetaminophen that might provide biological insights about the process of prostate cancer development and how this process could be slowed."
Use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), particularly long-term use, has been associated with modestly reduced risk of prostate cancer in some previous epidemiologic studies. Acetaminophen, a commonly used pain-reliever, is not traditionally considered an NSAID but can have anti-inflammatory effects.
For the current study, researchers led by Eric Jacobs, Ph.D., American Cancer Society epidemiologist, examined the association between acetaminophen use and prostate cancer incidence among 78,485 men in the Cancer Prevention Study II Nutrition Cohort. Information on acetaminophen use was obtained from a questionnaire completed at study enrollment in 1992 and updated using follow-up questionnaires in 1997 and every two years thereafter.
During follow-up from 1992 through 2007, there were 8,092 incident prostate cancer cases identified. Current regular use of acetaminophen (> 30 pills per month) for 5 years or more was associated with lower risk of overall prostate cancer (RR = 0.62, 95% CI 0.44-0.87) as well as lower risk of aggressive prostate cancer (RR = 0.49, 95% CI 0.27-0.88). Current regular use of < 5 years duration was not associated with prostate cancer risk.
"While the results of this observational study suggest that long-term regular acetaminophen use may be associated with lower prostate cancer risk, our findings require replication by other studies, and do not justify use of acetaminophen to prevent prostate cancer. Acetaminophen is considered relatively safe when used at recommended doses but unintentional acetaminophen overdose is an important cause of acute liver failure." said Dr. Jacobs. "Still, results of this study could lead to further research on acetaminophen that might provide biological insights about the process of prostate cancer development and how this process could be slowed."
Half of Prostate Cancers Could Potentially Benefit from New Type of Cancer Drugs
About half of prostate cancers have a genetic anomaly that appears to make tumor cells responsive to a new class of cancer-fighting drugs, a new study from the University of Michigan Comprehensive Cancer Center finds.
The drugs, called PARP inhibitors, are currently being tested in breast cancer patients with mutations in the BRCA1 and BRCA2 genes, which are found in up to 10 percent of all breast cancers.
Half of prostate cancers have a genomic rearrangement that causes the fusion of two genes called TMPRSS2 and ERG. This gene fusion, believed to be the triggering event of prostate cancer, was initially discovered in 2005 by U-M researchers led by Arul Chinnaiyan, M.D., Ph.D.
“This type of gene fusion occurs in about 50 percent of prostate cancers, but the genes involved have been notoriously difficult to target therapeutically. We found that instead of targeting the gene fusion product directly, we could block the function of critical interacting partners, such as PARP1,” says Chinnaiyan, a Howard Hughes Medical Institute researcher, director of the Michigan Center for Translational Pathology and S.P. Hicks Professor of Pathology at the U-M Medical School.
Chinnaiyan is the senior author of the current study, which appears in the May 17 issue of Cancer Cell.
“Our studies suggest that the total population of patients who could benefit from PARP inhibition could be significantly expanded,” says Chad Brenner, Ph.D. candidate at U-M, who is the first author on the study.
Working with prostate cancer models in cell lines and mice, researchers found that therapies using the PARP inhibitor Olaparib helped shrink tumors expressing the TMPRSS2:ERG gene fusion and blocked the ability of tumors to spread. Olaparib had no effect on tumors that did not have the gene fusion.
PARP inhibitors are not currently approved by the U.S. Food and Drug Administration, but initial trials in breast cancer patients indicate they can be administered safely and are well-tolerated.
Prostate cancer statistics: 217,730 Americans will be diagnosed with prostate cancer this year and 32,050 will die from the disease, according to the American Cancer Society.
Reference: Cancer Cell, Vol. 19, No. 5, pp. 664-678, May 17, 2011
The drugs, called PARP inhibitors, are currently being tested in breast cancer patients with mutations in the BRCA1 and BRCA2 genes, which are found in up to 10 percent of all breast cancers.
Half of prostate cancers have a genomic rearrangement that causes the fusion of two genes called TMPRSS2 and ERG. This gene fusion, believed to be the triggering event of prostate cancer, was initially discovered in 2005 by U-M researchers led by Arul Chinnaiyan, M.D., Ph.D.
“This type of gene fusion occurs in about 50 percent of prostate cancers, but the genes involved have been notoriously difficult to target therapeutically. We found that instead of targeting the gene fusion product directly, we could block the function of critical interacting partners, such as PARP1,” says Chinnaiyan, a Howard Hughes Medical Institute researcher, director of the Michigan Center for Translational Pathology and S.P. Hicks Professor of Pathology at the U-M Medical School.
Chinnaiyan is the senior author of the current study, which appears in the May 17 issue of Cancer Cell.
“Our studies suggest that the total population of patients who could benefit from PARP inhibition could be significantly expanded,” says Chad Brenner, Ph.D. candidate at U-M, who is the first author on the study.
Working with prostate cancer models in cell lines and mice, researchers found that therapies using the PARP inhibitor Olaparib helped shrink tumors expressing the TMPRSS2:ERG gene fusion and blocked the ability of tumors to spread. Olaparib had no effect on tumors that did not have the gene fusion.
PARP inhibitors are not currently approved by the U.S. Food and Drug Administration, but initial trials in breast cancer patients indicate they can be administered safely and are well-tolerated.
Prostate cancer statistics: 217,730 Americans will be diagnosed with prostate cancer this year and 32,050 will die from the disease, according to the American Cancer Society.
Reference: Cancer Cell, Vol. 19, No. 5, pp. 664-678, May 17, 2011
Rising PSA means prostate cancer is in patient's future
New study defuses controversy, shows why individual patient trends are critical
A man's rising PSA (prostate-specific antigen) level over several years – which had been seen as a possible warning sign of prostate cancer – has recently come under fire as a screening test because it sometimes prompts biopsies that turn out to be normal.
A new study, however, shows nearly 70 percent of men who had rising PSA levels and subsequent normal biopsies were eventually diagnosed with prostate cancer, according to research from Northwestern University Feinberg School of Medicine. The trend of a PSA level over several years is called PSA velocity.
"Our findings show an elevated and rising PSA level or velocity should lead a clinician to follow a patient more closely, even if he has a negative biopsy," said lead investigator William Catalona, M.D., director of the clinical prostate cancer program at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. "One negative biopsy isn't the end of the road."
The findings were presented May 18 at the American Urological Association 2011 Annual Meeting. Catalona is a professor of urology at the Feinberg School and a urologist at Northwestern Memorial Hospital.
PSA is a substance whose elevated levels can indicate prostate cancer but can also be caused by prostate inflammation or enlargement or other conditions. Catalona, known as the father of the PSA screening, was the first to show in 1991 that a simple blood test measuring PSA levels could be used to detect prostate cancer.
For the study, Northwestern researchers looked in their database at the history of 97 patients with a rising PSA trend (or velocity) who had a subsequent negative biopsy. Researchers found 66 percent of patients were eventually diagnosed with prostate cancer, 20 percent had a benign prostate, 8 percent had protatitis and 6 percent had premalignant lesions.
"This underscores the importance of using a patient's individual PSA trend when deciding whether to pursue a prostate biopsy," said co-investigator Gregory Auffenberg, M.D., a resident in urology at the Feinberg School. "It's not enough to only look at an individual PSA value when historical data is also available."
Lots of coffee = much lower the risk of lethal prostate cancer
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Drinking coffee is a fine way to start the day, many men would agree. For those worried about prostate cancer, it appears to be a great way to start the day.
The latest of many studies on whether a daily cup, or many cups, of java might lower a man’s risk of developing prostate cancer, especially lethal prostate cancer, falls on the side of coffee enthusiasts.
A Harvard School of Public Health study of nearly 48,000 men found that those who drank more than six cups of coffee per day had a 60% reduced risk of developing lethal prostate cancer compared with nondrinkers.
The reduction in lethal prostate cancer risk was similar between decaf and regular coffee drinkers. Thus, the researchers conclude, caffeine isn’t the wonder element -- good news for those who already consume far too much caffeine (you know who you are).
The results were published online Tuesday in the "Journal of the National Cancer Institute.
The researchers write in the discussion of their paper:
“An association between coffee and lower risk of advanced prostate cancer is biologically plausible. Coffee improves glucose metabolism, has anti-inflammatory and antioxidant effects, and affects sex hormone levels, all of which play roles in prostate cancer progression.”
But that’s not to say all men should consume cup after cup. Far from it. For those with benign prostatic hyperplasia, regular coffee can be problematic.
As this WebUrology article notes: “For men who have BPH, drinking coffee can be detrimental because caffeine can stimulate an already overactive bladder, which means it can increase urinary frequency and urgency and may even result in urge incontinence...Caffeine can also irritate the bladder because it is a theoxanthine, which is a family of drugs that includes theobromine (found in chocolate) and theophylline (found in tea).”
Drinking coffee is a fine way to start the day, many men would agree. For those worried about prostate cancer, it appears to be a great way to start the day.
The latest of many studies on whether a daily cup, or many cups, of java might lower a man’s risk of developing prostate cancer, especially lethal prostate cancer, falls on the side of coffee enthusiasts.
A Harvard School of Public Health study of nearly 48,000 men found that those who drank more than six cups of coffee per day had a 60% reduced risk of developing lethal prostate cancer compared with nondrinkers.
The reduction in lethal prostate cancer risk was similar between decaf and regular coffee drinkers. Thus, the researchers conclude, caffeine isn’t the wonder element -- good news for those who already consume far too much caffeine (you know who you are).
The results were published online Tuesday in the "Journal of the National Cancer Institute.
The researchers write in the discussion of their paper:
“An association between coffee and lower risk of advanced prostate cancer is biologically plausible. Coffee improves glucose metabolism, has anti-inflammatory and antioxidant effects, and affects sex hormone levels, all of which play roles in prostate cancer progression.”
But that’s not to say all men should consume cup after cup. Far from it. For those with benign prostatic hyperplasia, regular coffee can be problematic.
As this WebUrology article notes: “For men who have BPH, drinking coffee can be detrimental because caffeine can stimulate an already overactive bladder, which means it can increase urinary frequency and urgency and may even result in urge incontinence...Caffeine can also irritate the bladder because it is a theoxanthine, which is a family of drugs that includes theobromine (found in chocolate) and theophylline (found in tea).”
Brisk walking helps men fight prostate cancer
A study of 1,455 U.S. men diagnosed with early-stage prostate cancer has found a link between brisk walking and lowered risk of prostate cancer progression, according to scientists at the University of California, San Francisco and the Harvard School of Public Health.
The scientists found that men who walked briskly -- at least three miles per hour -- for at least three hours per week after diagnosis were nearly 60 percent less likely to develop biochemical markers of cancer recurrence or need a second round of treatment for prostate cancer.
"The important point was the intensity of the activity – the walking had to be brisk for men to experience a benefit," said Erin Richman, ScD, a postdoctoral fellow at UCSF who is the first author on the study, published today in the journal Cancer Research. "Our results provide men with prostate cancer something they can do to improve their prognosis."
An earlier study, published earlier this year by UCSF's June Chan, ScD, and collaborators at the Harvard School of Public Health, showed that physical activity after diagnosis could reduce disease-related mortality in a distinct population of men with prostate cancer. The new study complements this finding, as it was the first to focus on the effect of physical activity after diagnosis on early indications of disease progression, such as a rise in prostate-specific antigen (PSA) blood levels.
"Our work suggests that vigorous physical activity or brisk walking can have a benefit at the earlier stages of the disease," said Chan, the Steven and Christine Burd-Safeway Distinguished Professor at UCSF and senior author of both studies.
COMMON FORM OF CANCER AMONG MEN
After skin cancer, prostate cancer is the most commonly diagnosed type of cancer among men in the United States, and more than 217,000 U.S. men are diagnosed with the disease every year according to the National Cancer Institute. Last year alone 32,050 men died from the disease.
Vigorous exercise and brisk walking have been consistently shown to have significant benefits on cardiovascular health, diabetes, and many other diseases. Previous studies have also shown the benefit of regular physical activity for disease outcomes in breast and colon cancer, but this is one of the first studies to demonstrate such a benefit for men with prostate cancer.
The participants in this study were selected were a subset of a larger group of 14,000 men with prostate cancer who are enrolled in a long-term, nationwide prostate cancer registry study known as the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE™), led by Peter Carroll, MD, MPH, who is the chair of the Urology Department at UCSF and an author of the study.
A particular strength of this study is the focus on early recurrence of prostate cancer, which occurs before men may experience painful symptoms of prostate cancer metastases, a frequent cause for men to decrease their usual physical activity. Additionally, the researchers reported that the benefit of physical activity was independent of the participants' age at diagnosis, type of treatment and clinical features of their disease at diagnosis.
Asked whether she would recommend walking for all men who are diagnosed with prostate cancer, Dr. Chan said yes -- but emphasized that the walking must be brisk.
"Our results suggest that it is important to engage in exercise that gets your heart rate up a little bit," she advised.
The scientists found that men who walked briskly -- at least three miles per hour -- for at least three hours per week after diagnosis were nearly 60 percent less likely to develop biochemical markers of cancer recurrence or need a second round of treatment for prostate cancer.
"The important point was the intensity of the activity – the walking had to be brisk for men to experience a benefit," said Erin Richman, ScD, a postdoctoral fellow at UCSF who is the first author on the study, published today in the journal Cancer Research. "Our results provide men with prostate cancer something they can do to improve their prognosis."
An earlier study, published earlier this year by UCSF's June Chan, ScD, and collaborators at the Harvard School of Public Health, showed that physical activity after diagnosis could reduce disease-related mortality in a distinct population of men with prostate cancer. The new study complements this finding, as it was the first to focus on the effect of physical activity after diagnosis on early indications of disease progression, such as a rise in prostate-specific antigen (PSA) blood levels.
"Our work suggests that vigorous physical activity or brisk walking can have a benefit at the earlier stages of the disease," said Chan, the Steven and Christine Burd-Safeway Distinguished Professor at UCSF and senior author of both studies.
COMMON FORM OF CANCER AMONG MEN
After skin cancer, prostate cancer is the most commonly diagnosed type of cancer among men in the United States, and more than 217,000 U.S. men are diagnosed with the disease every year according to the National Cancer Institute. Last year alone 32,050 men died from the disease.
Vigorous exercise and brisk walking have been consistently shown to have significant benefits on cardiovascular health, diabetes, and many other diseases. Previous studies have also shown the benefit of regular physical activity for disease outcomes in breast and colon cancer, but this is one of the first studies to demonstrate such a benefit for men with prostate cancer.
The participants in this study were selected were a subset of a larger group of 14,000 men with prostate cancer who are enrolled in a long-term, nationwide prostate cancer registry study known as the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE™), led by Peter Carroll, MD, MPH, who is the chair of the Urology Department at UCSF and an author of the study.
A particular strength of this study is the focus on early recurrence of prostate cancer, which occurs before men may experience painful symptoms of prostate cancer metastases, a frequent cause for men to decrease their usual physical activity. Additionally, the researchers reported that the benefit of physical activity was independent of the participants' age at diagnosis, type of treatment and clinical features of their disease at diagnosis.
Asked whether she would recommend walking for all men who are diagnosed with prostate cancer, Dr. Chan said yes -- but emphasized that the walking must be brisk.
"Our results suggest that it is important to engage in exercise that gets your heart rate up a little bit," she advised.
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