MUSHROOM-SUPPLEMENTED SOYBEAN EXTRACT SHOWS THERAPEUTIC PROMISE FOR ADVANCED PROSTATE CANCER

A natural, nontoxic product called genistein-combined polysaccharide, or GCP, which is commercially available in health stores, could help lengthen the life expectancy of certain prostate cancer patients, UC Davis researchers have found.

Men with prostate cancer that has spread to other parts of the body, known as metastatic cancer, and who have had their testosterone lowered with drug therapy are most likely to benefit. The study, recently published in Endocrine-Related Cancer, was conducted in prostate cancer cells and in mice.

Lowering of testosterone, also known as androgen-deprivation therapy, has long been the standard of care for patients with metastatic prostate cancer, but life expectancies vary widely for those who undergo this treatment. Testosterone is an androgen, the generic term for any compound that stimulates or controls development and maintenance of male characteristics by binding to androgen receptors.

The current findings hold promise for GCP therapy as a way to extend life expectancy of patients with low response to androgen-deprivation therapy.

Paramita Ghosh, an associate professor in the UC Davis School of Medicine, led the pre-clinical study with a team that included UC Davis Comprehensive Cancer Center Director Ralph de Vere White, a UC Davis distinguished professor of urology. Ruth Vinall in the UC Davis Department of Urology and Clifford Tepper in the UC Davis Department of Biochemistry and Molecular Medicine directed the studies in mice; Ghosh’s laboratory conducted the cell studies.

The research focused on GCP, a proprietary extract cultured from soybeans and shiitake mushrooms and marketed by Amino-Up of Sapporo, Japan. Researchers found that the combination of the compounds genistein and daidzein, both present in GCP, helps block a key mechanism used by prostate cancer cells to survive in the face of testosterone deprivation.

The research team had earlier shown that when a patient’s androgen level goes down, cancerous prostate cells kick out a protein known as filamin A, which is otherwise attached to the androgen receptor in the cell’s nucleus. The androgen receptor regulates growth of prostate cancer cells. Once filamin A leaves the cancerous cell’s nucleus, that cell no longer requires androgens to survive. Thus, loss of filamin A allows these cells to survive androgen deprivation, at and the cancer essentially becomes incurable.

The paper, titled “Enhancing the effectiveness of androgen deprivation in prostate cancer by inducing Filamin A nuclear localization,” shows for the first time that GCP keeps filamin A in the nucleus. As long as this protein remains attached to the androgen receptor, the cancerous cells need androgens to survive and grow. They die off when starved of androgens, thus prolonging the effects of androgen deprivation, which ultimately prolongs the patient’s life.

The team’s hypothesis is that metastatic prostate cancer patients with the weakest response to androgen-deprivation therapy could be given GCP concurrently with androgen deprivation therapy to retain Filamin A in the nucleus, thereby allowing cancer cells to die off.

De Vere White is now pursuing funding to begin GCP human clinical trials. Because GCP is a natural product rather than a drug, and requires fewer government approvals, it’s expected that these trials will proceed rapidly once funded.

“We should know within the first eight months or so of human clinical trials if GCP works to reduce PSA levels,” says de Vere White, referring to prostate-specific antigen levels, a tumor marker to detect cancer. “We want to see up to 75 percent of metastatic prostate cancer patients lower their PSA levels, and GCP holds promise of accomplishing this goal. If that happens, it would probably be a greater therapy than any drug today.”

New Compound Holds High Promise in Battling Kidney Cancer

Chemists at the University of California, Riverside have developed a compound that holds much promise in the laboratory in fighting renal (kidney) cancer.

Named TIR-199, the compound targets the "proteasome," a cellular complex in kidney cancer cells, similar to the way the drug bortezomib, approved by the Food and Drug Administration, targets and inhibits the proteasome in multiple myeloma cells, a cancer coming from bone marrow.

Michael Pirrung, a distinguished professor of chemistry at UC Riverside, announced the development of TIR-199 in a lecture he gave on Feb. 19 at the 5th International Conference on Drug Discovery and Therapy, held in Dubai, UAE.

Operating like the garbage dump of a cell, the proteasome breaks down proteins. Drugs that block the action of proteasomes are called proteasome inhibitors, and have been shown to have activity against a variety of cancer cell lines, albeit with mixed results. For example, bortezomib, though effective against multiple myeloma, has many side effects because cells other than bone marrow cells are affected.

"The novel feature of our new proteasome inhibitor, TIR-199, is that it is nearly as potent as bortezomib, but is selective in inhibiting the growth of only renal cancer cell lines," Pirrung said. "It's what makes TIR-199 attractive."

The TIR-199 research project at UC Riverside began about four years ago after a multidisciplinary, international team reported on a class of compounds that act on the proteasome. These compounds are the "syringolin" natural products -- such as a compound produced naturally by the wheat-infecting bacterium Pseudomonas syringae. TIR-199 is a synthetic relative of syringolin.

"At UCR we began to work on, and completed the synthesis of, two compounds from this class of compounds," Pirrung said. "Of the two, TIR-199 showed most promise."

Pirrung's lab first shipped TIR-199 samples to the University of Hawaii, Hilo, where André Bachmann, an associate professor of pharmaceutical sciences and Pirrung's collaborator, studied TIR-199 in test-tube assays for how it worked against the proteasome. Bachmann then tested the compound against a limited number of cancer cell lines that showed that TIR-199 was effective against the cancer cells. What remained unclear, however, was if TIR-199 was toxic to normal cells.

Encouraged by these results, Pirrung submitted TIR-199 samples to the National Cancer Institute at the National Institutes of Health, where the compound was subjected to a rigorous 60-cell screening used routinely to test compounds for their effectiveness in battling 60 kinds of cancer, including leukemia, lung, colon, brain, breast, ovarian prostate and renal cancers.

"We were very excited when the NCI informed us that TIR-199 has excellent potential to be moved to drug development because of its selective activity against renal cancer," Pirrung said. "This is good news also because the NCI scientists told us there really are no good drugs out there to fight renal cancer."

Next, the NCI will test TIR-199 on cells grown in a hollow fiber that partially mimics the body by offering a three-dimensional environment. If the test results are positive, TIR-199 will be tested on mice.

The UCR Office of Technology Commercialization has filed a patent application on TIR-199 and is currently seeking partners in industry interested in developing the compound commercially. Several biotechnology companies have already shown interest.

"We still have to fine-tune TIR-199 in the lab because some aspects -- certain structural elements within it -- make it easily metabolized," Pirrung said. "But now that we have a good handle on how structural changes in the compound affect anticancer activity and how the parent drug binds to the proteasome, we are pretty confident of making a better version -- the second generation -- of TIR-199."

The project was funded by a grant from the University of California Institute for Mexico and the United States (UC MEXUS), to Tannya Ibarra-Rivera, a former postdoctoral researcher in Pirrung's lab who helped discover TIR-199 and after whose initials the compound is named; and to Pirrung from the UC Cancer Research Coordinating Committee.

Men at ‘High’ Skeletal Risk Prior to Prostate Cancer Hormone Therapy Likely to Have More Fractures After Treatment

In what is believed to be the first study to describe the impact on men with a ‘high’ risk of bone fracture who are receiving long-term androgen deprivation therapy (ADT) for prostate cancer, new research from The Cancer Institute of New Jersey shows this population to have a higher fracture incidence following treatment completion. The findings, published in the latest online version of BJU International (doi:10.1111/j.1464-410X.2012.11758.x), also show that men who experienced a fracture had a 1.38-fold higher mortality risk than those who did not. The Cancer Institute of New Jersey is a Center of Excellence of the University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School (RWJMS).

Men with localized prostate cancer who have underlying health conditions often receive this type of therapy with the hope to shrink or delay growth of their cancer, because they are considered inappropriate candidates for more aggressive therapies such as surgery or radiation. Previous studies have shown an association between the receipt of ADT for prostate cancer and an increased risk of bone fracture and other skeletal complications, such as a decrease in bone mineral density. The investigators at The Cancer Institute of New Jersey further explored the impact of this treatment on men already deemed to be at high risk for fracture prior to receiving therapy.

Using the population-based Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database, researchers reviewed information on demographics and tumor characteristics from 75,994 men aged 66 and older who were diagnosed as having localized prostate cancer from 1992 to 2007. All of the SEER registries hold the highest level of certification of data quality. A risk assessment scale for baseline skeletal complications - including fracture - was created, utilizing the presence of certain conditions within one year prior to cancer diagnosis. These conditions included diabetes, alcohol and cigarette use, paralysis, and liver disease.

Investigators found that during a 12-year follow up, more than 58 percent of men deemed at high fracture risk prior to treatment and 38 percent considered at low risk developed at least one fracture following ADT. The research also showed that men with a high baseline risk had a higher probability of receiving ADT (52.1 percent) compared to those with a low baseline risk (38.2 percent). It was also determined that those men receiving ADT by itself were likely to have a stronger dose than those who received ADT in combination with other treatments for their prostate cancer. Mortality risk was found to be 40 percent higher within two years after experiencing a fracture.

“Our findings suggest that treating men having a high baseline risk of fracture with long-term androgen deprivation therapy may have serious adverse consequences,” said senior author Grace Lu-Yao, PhD, MPH, cancer epidemiologist at The Cancer Institute of New Jersey and professor of medicine at Robert Wood Johnson Medical School and of epidemiology at UMDNJ-School of Public Health. “We anticipate the results of this study will prompt further examination of a patient’s baseline-risk of fracture and skeletal complications prior to administering this course of therapy.”

The authors note the use of bisphosphonates, which are effective in preventing bone loss in patients with prostate cancer receiving ADT, was not available in the SEER-Medicare linked data. Information regarding a patient’s height and weight, which can be considered risk factors for skeletal complications, also was not available. Data on men younger than 66 were not examined. Despite these limitations, Dr. Lu-Yao, says their investigation shines new light on a large subset of men who commonly receive ADT.

Change in PSA levels over time can help predict aggressive prostate cancer

Measurements taken over time of prostate specific antigen, the most commonly used screening test for prostate cancer in men, improve the accuracy of aggressive prostate cancer detection when compared to a single measurement of PSA, according to a Kaiser Permanente study published today in the British Journal of Urology International.

The retrospective study examined the electronic health records of nearly 220,000 men ages 45 and older over a 10-year period who had at least one PSA measurement and no previous diagnosis of prostate cancer. The study found that annual percent changes in PSA more accurately predicted the presence of aggressive prostate cancer when compared to single measurements of PSA alone, but only marginally improved the prediction of prostate cancer overall.

"The use of a single, elevated PSA level to screen for prostate cancer is considered controversial given the questionable benefits of PSA screening on prostate cancer mortality. The screening may also result in unnecessary prostate biopsies and subsequent treatments for localized prostate cancer, as it does not distinguish well between slow-growing and aggressive disease," said Lauren P. Wallner, PhD, MPH, study lead author and post-doctoral research fellow at Kaiser Permanente Southern California's Department of Research & Evaluation. "Our study demonstrates that repeated measurements of PSA over time could provide a more accurate – and much needed – detection strategy for aggressive forms of prostate cancer."

Men in the study were also found to experience a 2.9 percent change in PSA levels per year on average and that the rate of change in PSA increased modestly with age.

"The results of this study could provide clinicians with a better prostate cancer preventive strategy that could help differentiate between men with an aggressive form of the disease and those who have slow-growing, indolent cancer that may not necessarily merit treatment," said Wallner. "While we do not suggest that patients proactively seek out additional PSA measurements, men who already have had multiple PSAs may consider discussing the change in their PSA levels with their clinician when determining future treatment strategies."

The PSA test measures the level of prostate specific antigen, a substance made by the prostate, in a man's blood. It is one of the most commonly used tests to screen for prostate cancer, according to the Centers for Disease Control and Prevention. As a rule, the higher the PSA level in the blood, the more likely a prostate problem is present. But many factors, such as age, race, and non-cancerous conditions can affect PSA levels. The CDC and other federal agencies follow the prostate cancer screening recommendations set forth by the U.S. Preventive Services Task Force, which recommends against PSA-based screening for men who do not have symptoms. Kaiser Permanente guidelines include a recommendation that men age 40 and older should discuss the PSA test and rectal exam with their physician.

Aside from non-melanoma skin cancer, prostate cancer is the most common cancer among men in the United States, according to the CDC. In 2008 (the most recent year numbers are available), nearly 215,000 men in the United States were diagnosed with prostate cancer and more than 28,000 men died from the disease. Prostate cancer is the second most common cause of death from cancer among white, African American, American Indian/Alaska Native and Hispanic men, and is more common in African-American men than white men, according to the CDC.

How prostate cancer therapies compare by cost and effectiveness

Surgery ranks as the most cost-effective type of treatment, according to UCSF-led study


The most comprehensive retrospective study ever conducted comparing how the major types of prostate cancer treatments stack up to each other in terms of saving lives and cost effectiveness is reported this week by a team of researchers at the University of California, San Francisco (UCSF).

Appearing in the British Journal of Urology International, the work analyzed 232 papers published in the last decade that report results from clinical studies following patients with low-, intermediate- and high-risk forms of prostate cancer who were treated with one or more of the standard treatments – radiation therapy, surgery, hormone therapies and brachytherapy.

The analysis shows that for people with low-risk prostate cancer, the various forms of treatment vary only slightly in terms of survival – the odds of which are quite good for men with this type of cancer, with a 5-year cancer-specific survival rate of nearly 100 percent. But the cost of radiation therapy is significantly more expensive than surgery for low-risk prostate cancer, they found.

For intermediate- and high-risk cancers, both survival and cost generally favored surgery over other forms of treatment – although combination external-beam radiation and brachytherapy together were comparable in terms of quality of life-adjusted survival for high-risk prostate cancer.

"Our findings support a greater role for surgery for high-risk disease than we have generally seen it used in most practice settings," said urologist Matthew Cooperberg, MD, MPH who led the research. Cooperberg is an assistant professor of urology and epidemiology and biostatistics in the UCSF Helen Diller Family Comprehensive Cancer Center.

The UCSF Helen Diller Family Comprehensive Cancer Center is one of the country's leading research and clinical care centers, and it is the only comprehensive cancer center in the San Francisco Bay Area.

Many Treatment Options, but Few Cost Analyses

Localized prostate cancer accounts for about 81 percent of the quarter-million cases of prostate cancers that occur in the United States every year, according to the National Cancer Institute. It is defined by tumors that have not metastasized and spread outside the prostate gland to other parts of the body.

There are multiple types of treatment for this form of the disease, including various types of surgery (open, laparoscopic or robot-assisted); radiation therapy (dose-escalated three-dimensional conformal radiation therapy, intensity-modulated radiation therapy and brachytherapy); hormone therapies; and combinations of each of these. Many men with low-risk prostate cancer do not need any of these treatments, and can be safely observed, at least initially.

Treatment plans for localized prostate cancer often vary dramatically from one treatment center to another. As Cooperberg put it, one person may have surgery, while someone across town with a very similar tumor may have radiation therapy, and a third may undergo active surveillance. All treatment regimens may do equally well.

"There is very little solid evidence that one [approach] is better than another," said Cooperberg. The motivation for the new study, however, was that there are also few data examining the differences in terms of cost-effectiveness – the price to the health care system for every year of life gained, with adjustment for complications and side effects of treatments.

The new study was the most comprehensive cost analysis ever, and it compared the costs and outcomes associated with the various types of treatment for all forms of the disease, which ranged from $19,901 for robot-assisted prostatectomy to treat low-risk disease, to $50,276 for combined radiation therapy for high-risk disease.

The study did not consider two other approaches for dealing with prostate cancer: active surveillance, where patients with low-risk cancer are followed closely with blood tests and biopsies and avoid any initial treatment; and proton therapy, which is much more expensive and has already been shown in multiple studies not to be cost-effective, said Cooperberg.

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The article, "Primary treatments for clinically localised prostate cancer: a comprehensive lifetime cost-utility analysis" is authored by Matthew R. Cooperberg, Naren R. Ramakrishna, Steven B. Duff, Kathleen E. Hughes, Sara Sadownik, Joseph A. Smith and Ashutosh K. Tewari. It was published online on Dec. 28, 2012 by the British Journal of Urology International. The article can be accessed at: http://dx.doi.org/10.1111/j.1464-410X.2012.11597.x

Resveratrol Could Be Key to Fighting Prostate Cancer

Resveratrol, a compound found commonly in grape skins and red wine, has been shown to have several beneficial effects on human health, including cardiovascular health and stroke prevention. Now, a University of Missouri researcher has discovered that the compound can make prostate tumor cells more susceptible to radiation treatment, increasing the chances of a full recovery from all types of prostate cancer, including aggressive tumors.

"Other studies have noted that resveratrol made tumor cells more susceptible to chemotherapy, and we wanted to see if it had the same effect for radiation therapy," said Michael Nicholl, an assistant professor of surgical oncology in the MU School of Medicine. "We found that when exposed to the compound, the tumor cells were more susceptible to radiation treatment, but that the effect was greater than just treating with both compounds separately."

Prostate tumor cells contain very low levels of two proteins, perforin and granzyme B, which can function together to kill cells. However, both proteins need to be highly "expressed" to kill tumor cells. In his study, when Nicholl introduced resveratrol into the prostate tumor cells, the activity of the two proteins increased greatly. Following radiation treatment, Nicholl found that up to 97 percent of the tumor cells died, which is a much higher percentage than treatment with radiation alone.

"It is critical that both proteins, perforin and granzyme B, are present in order to kill the tumor cells, and we found that the resveratrol helped to increase their activity in prostate tumor cells," Nicholl said. "Following the resveratrol-radiation treatment, we realized that we were able to kill many more tumor cells when compared with treating the tumor with radiation alone. It's important to note that this killed all types of prostate tumor cells, including aggressive tumor cells."

Resveratrol is present in grape skins and red wine and available over-the-counter in many health food sections at grocery stores. However, the dosage needed to have an effect on tumor cells is so great that many people would experience uncomfortable side effects.

"We don't need a large dose at the site of the tumor, but the body processes this compound so efficiently that a person needs to ingest a lot of resveratrol to make sure enough of it ends up at the tumor site. Because of that challenge, we have to look at different delivery methods for this compound to be effective," Nicholl said. "It's very attractive as a therapeutic agent since it is a natural compound and something that most of us have consumed in our lifetimes."

Nicholl said that the next step would be to test the procedure in an animal model before any clinical trials can be initiated. Nicholl's studies were published in the Journal of Andrology and Cancer Science. The early-stage results of this research are promising. If additional studies, including animal studies, are successful within the next few years, MU officials will request authority from the federal government to begin human drug development (this is commonly referred to as the "investigative new drug" status). After this status has been granted, researchers may conduct human clinical trials with the hope of developing new treatments for cancer.

Depression increased bladder cancer mortality

As part of an ongoing, large-scale epidemiologic study of bladder cancer, Chen and colleagues collected clinical and mental health information on 464 patients with bladder cancer. They assessed patients' depression levels with the Center for Epidemiologic Studies Depression Scale (CES-D).

Depression symptoms alone affected mortality: Patients with CES-D scores of 16 or greater had a median survival time of 58 months, while those with scores below 16 had a median survival time longer than 200 months. In addition, patients with CES-D scores of 16 or greater had a 1.89-fold increased risk for all-cause mortality compared with patients with CES-D scores less than 16.

In addition, the researchers pointed to evidence that smoking cessation, weight loss and increased physical activity can potentially improve survival.

"In terms of building a prediction model for bladder cancer mortality, current models only focus on clinical variables, such as treatment and tumor stage and grade," Chen said. "Our study suggests that psychological factors and perhaps lifestyle changes could be included in this prediction model."