Wednesday, June 29, 2011



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.

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."

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."

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

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


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.


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.

Thursday, June 2, 2011

IMRT cuts GI side effects from prostate cancer in half vs. 3D-CRT

Intensity modulated radiation therapy, a newer, more precise form of radiation therapy, causes fewer gastrointestinal side effects when combined with hormone therapy than using three-dimensional radiation therapy, according to a study published in the June issue of the International Journal of Radiation Oncology•Biology•Physics, the official scientific journal of the American Society for Radiation Oncology (ASTRO).

Three-dimensional radiation therapy (3D-CRT) combined with hormone therapy has been proven very effective at treating men with intermediate to high-risk prostate cancer. However, these treatments can cause very uncomfortable gastrointestinal side effects due to exposure of the rectum to radiation during treatment.

Researchers at Fox Chase Cancer Center in Philadelphia conducted a study to see if IMRT, which allows doctors to better concentrate radiation in the prostate and limit rectal exposure, reduces the side effects while continuing to deliver the necessary radiation to successfully treat the cancer.

Two hundred ninety-three men were studied – 170 received 3D-CRT and 123 received IMRT. With a mean follow-up of 86 months, a multivariate analysis shows that patients treated with 3D-CRT were more than twice as likely to develop gastrointestinal toxicity compared to patients treated with IMRT.

"The use of IMRT significantly reduces the risk of late GI toxicity in men undergoing concurrent radiation therapy and hormone therapy for prostate cancer," Mark Buyyounounski, MD, MS, a radiation oncologist at Fox Chase Cancer Center, said. "I encourage men with prostate cancer receiving hormone therapy and radiation therapy to talk their doctors about whether IMRT has advantages over other types of radiation therapy."

For more information on radiation therapy for prostate cancer, visit

Higher doses of radiation in fewer treatments proved safe

In a multicenter clinical trial, UT Southwestern Medical Center researchers have found that higher doses of stereotactic radiation therapy requiring fewer treatments are safe and effective for patients with low-to-intermediate-risk prostate cancer.

Results of the trial, available in the Journal of Clinical Oncology, showed that stereotactic body radiation therapy (SBRT), which delivers ultra-precise radiation, was effective in treating patients with localized prostate cancer in five 30-minute sessions every other day over two weeks. That compares to the typical radiation protocol for prostate cancer of 42 to 45 daily treatments administered over eight to nine weeks.

"We were trying to develop a fast, convenient, outpatient, non-invasive treatment," said Dr. Robert Timmerman, vice chairman of radiation oncology and professor of neurological surgery and senior author of the study. "In the low-risk population, there are a lot of good options, but none of them are altogether convenient. The most convenient treatment would finish quickly without the need for a prolonged recovery."

SBRT has been used in the last decade to treat patients with lung, liver and brain cancers. The current study tested whether high-potency treatments would work in a moving target like the prostate, which moves considerably due to normal bladder and bowel filling.

"We're trying to kill the prostate cancer, but without injuring the urethra, the bladder or the rectum," Dr. Timmerman said. "Each treatment had to be very potent in order to get the full radiation effect in only five treatments."

To avoid injury to healthy tissue, researchers used beams of radiation that were just millimeters larger than the target itself. That narrow scope helped avoid consequences such as rectal injury, impotence and difficulty urinating.

Prostate cancer is the most common cancer in men, with some 200,000 diagnosed each year in the U.S. About half of those who are treated undergo radiation therapy, typically for eight weeks. Not everyone is cured, however, because some tumors are resistant to radiation.

In the current clinical trial, researchers tested escalating doses for safety levels in 45 patients enrolled from November 2006 to May 2009. In a 90-day follow-up procedure, they looked at how much injury occurred in adjacent areas, including the rectum or urethra, and any changes to the patients' quality of life.

"There were a few more complications associated with higher doses, but they were fairly predictable and rarely severe," said Dr. Yair Lotan, associate professor of urology and a co-author of the study. "By giving these higher doses, we might be able to kill more resistant tumors with shorter treatments."

In the next stage of the clinical trial, a larger group of patients will be treated at one dosage level, and follow-up will be 18 months.

Antifungal drug delays need for chemo in advanced prostate cancer

The oral antifungal drug itraconazole, most commonly used to treat nail fungus, may keep prostate cancer from worsening and delay the need for chemotherapy in men with advanced disease. Details of the finding, from a clinical trial led by Johns Hopkins experts, are scheduled for presentation on Saturday, June 4 at the 2011 American Society of Clinical Oncology (ASCO) annual meeting (abstract #4532).

Currently, the drug is approved to treat fungal infections in nails and other organs. Serious side effects can include heart failure, and Johns Hopkins experts caution that itraconazole needs further study before it can be considered for prostate cancer treatment.

Identified as a potential anticancer drug after Hopkins scientists scoured a database of more than 3,000 FDA-approved drugs, itraconazole appears to block tumor blood vessel growth -- the only drug in its class to do so -- much like the anticancer drug bevacizumab (Avastin). The antifungal also disrupts a key cancer-initiating biological pathway called Hedgehog. Laboratory testing by Johns Hopkins scientist Jun Liu, Ph.D., has shown that human prostate tumors implanted in mice shrink when treated with itraconazole.

"The most effective therapy we have right now for metastatic prostate cancer is hormone therapy, and when it doesn't work, the next step is usually chemotherapy," says Emmanuel Antonarakis, M.D., assistant professor of oncology at the Johns Hopkins Kimmel Cancer Center. In a search for compounds that could put off chemotherapy, the Johns Hopkins team turned to itraconazole.

For the study, patients with prostate cancer that had spread to other organs and did not respond to hormone therapy were randomly assigned to receive low or high doses of itraconazole.

Over 24 weeks of daily treatment with oral itraconazole, the investigators tracked the length of time for each patient's prostate cancer to worsen (called progression-free survival). Evidence of worsening disease was measured by a 25 percent increase in their blood level of prostate specific antigen (PSA), a marker for prostate cancer.

Early in the trial, preliminary analysis of 17 men receiving low doses of itraconazole showed that only two of them (11.8 percent) had stable or declining PSA. Because of the limited response, no further men were given low doses of the drug.

However, 11 of 24 (48.4 percent) men taking high doses of itraconazole had stable or declining PSA levels lasting at least 24 weeks. In addition, nearly a third of men taking the high dose had PSA reductions of 30 percent or more. Metastatic prostate cancer patients receiving no treatment typically would worsen in eight to 12 weeks, according to Antonarakis.

The investigators also found that 12 of 14 men taking high doses of itraconazole had lower levels of circulating tumor cells present in their blood after therapy, compared with their baseline levels.

Seven patients experienced side effects, including low potassium, hypertension and fluid retention, but the problems were resolved with potassium replacement pills, anti-hypertension drugs, and diuretics.

"We also tested whether itraconazole acted as hormone therapy by tracking levels of testosterone and DHEA (a testosterone derivative) in the blood, and we found no reductions of either testosterone or DHEA," says Antonarakis. "This finding shows that itraconazole is not just another hormone therapy, and has a unique mechanism of action."

Antonarakis and colleagues next plan to examine blood and skin samples taken from study participants specifically to look for levels of proteins linked to tumor blood vessel formation and the Hedgehog pathway.

"With these results, we believe that high-dose itraconazole is worth studying in a larger group of men with advanced prostate cancer," adds Antonarakis.