About Research Accomplishments
The Prostate Cancer Foundation has been a major catalyst for many of the scientific advances in prostate cancer research since 1993. PCF has awarded more than 2,000 projects that offer hope for improving outcomes in patients with prostate cancer. These high-impact projects include clinical research to evaluate new drugs, novel treatment strategies for prostate cancer and basic science research to better understand the biology of prostate cancer.
PCF grant funding has led directly to many advances in comprehending the underlying mechanisms of prostate cancer, including identification of the genetic changes that might cause cells in the prostate to become cancerous; interference with the development of blood vessels that feed nutrients to cancer cells; identification of prostate cell surface markers that can be targeted to destroy cancerous cells; and development of analytical methods that identify the proteins in blood or the prostate that correlate to treatment effect or behavior of the cancer cell.
At the same time, the Prostate Cancer Foundation has funded key clinical trials as part of its efforts to shorten the time between drug development and FDA approval. Since 1993, the PCF has funded the discovery and/or early clinical development of such diverse agents as monoclonal antibodies that directly target prostate cancer cells, bisphosphonates for the prevention and treatment of bone metastases, and endothelin-A receptor antagonists. Importantly, six of the nine new drugs for prostate cancer patients that have gained FDA approval since 2002, were supported by PCF-funding at some point during their discovery or development. Each of these agents is poised to make a significant impact on the outcomes of patients with prostate cancer.
The following discoveries were all made by Prostate Cancer Foundation-supported scientists:
Genetics – Drs. Kathleen Cooney, MD, at the University of Michigan, and William Issacs, PhD, at Johns Hopkins, made the first-ever discovery of an inherited mutation associated with increased risk for developing prostate cancer. Assessment of this gene, HOXB13, will allow identification of men with significantly increased risk for developing prostate cancer and generate new insights into disease biology.
Biomarkers – Drs. Scott Tomlins, MD, PhD, and Arul Chinnaiyan, MD, PhD, of the University of Michigan, developed a non-invasive, highly specific urine test that predicts the presence of clinically relevant prostate cancer in men with elevated PSA levels. TMPRSS2:ERG is a prostate cancer-specific chromosomal fusion that occurs in ~50% of prostate cancers, and was first discovered by these researchers. PCA3 is gene that is highly expressed by prostate cancers. This test, Mi-Prostate Score (MiPS), detects the RNA of TMPRSS2:ERG and PCA3 in the urine, and incorporates the results with PSA levels, for enhanced stratification of a patient’s risk of having aggressive prostate cancer, which may help men to avoid unnecessary biopsies and procedures. The MiPS test is now commercially available from the University of Michigan MLabs.
Targeted Therapies – Drs. Howard Scher, MD, of Memorial Sloan-Kettering Cancer Center, and Johann de Bono, MD, PhD, of the Royal Marsden Hospital, UK, led efforts in organizing the phase III clinical trials that resulted in FDA approval of two new therapies that target different aspects of androgen receptor activity, enzalutamide (Xtandi) and abiraterone acetate (Zytiga), for use in patients with metastatic castrate-resistant prostate cancer. Ongoing clinical trials are testing the efficacy of these drugs at different stages of disease, and in combination with various other treatment modalities.
Targeted Therapies – Drs. William Polkinghorn, MD, of Memorial Sloan-Kettering Cancer Center, and Karen Knudsen, PhD, Thomas Jefferson University, both discovered the reason that androgen-deprivation therapy and ionizing radiation are synergistic in the treatment of prostate cancer patients: the androgen receptor directly activates genes that repair DNA, so unless the androgen receptor is inhibited, prostate cancer cells can more easily resist death caused by radiation – which is due to DNA damage. Multiple clinical trials testing drugs targeting DNA-repair proteins (PARP1) in prostate cancer, led by PCF-funded researchers are ongoing, and trials with drugs targeting other DNA-repair proteins are being planned.
Targeted Therapies – Drs. Felix Feng, MD, and Maha Hussain, MD, of the University of Michigan, are leading first-in-field clinical trials to test the efficacy of combining a drug targeting a cancer cell growth regulator, CDK4/6 (PD-0332991), with androgen deprivation therapy (bicalutamide). Expression of the Retinoblastoma (Rb) protein by prostate cancer cells may predict which patients will respond to this therapy and is being assessed as part of these trials.
Exercise – Dr. Lorelei Mucci, ScD, of the Harvard School of Public Health, has discovered a potential reason why energetic physical activity increases survival time in men diagnosed with prostate cancer. Regular brisk walking (>3 mph) was associated with more normally shaped blood vessels in prostate tumors, a factor shown to lower the risk of lethal disease. This study emphasizes how regular exercise directly benefits prostate cancer patients.
Nutrition – Drs. June Chan, ScD, and Stacey Kenfield, ScD, of the University of California, San Francisco, found that dietary intake of vegetable fats reduced the risk of progressing to lethal prostate cancer in men who had been diagnosed with nonmetastatic prostate cancer. Higher consumption of carbohydrates and animal fats was associated with increased risk of progression to lethal disease. Certain types of dietary fats may prevent vs. enhance prostate cancer progression.
Prevention – Dr. Elizabeth Platz, ScD, of the Johns Hopkins Bloomberg School of Public Health, discovered that men who took statins significantly cut their risk of developing advanced prostate cancers, particularly metastatic and lethal cancers, by half or more. The risk of developing indolent cancers however, was unaffected. Statins are commonly prescribed cholesterol-lowering medications used to prevent heart attacks and strokes. These studies indicate that statins may prevent the progression of prostate cancers from indolent to clinically relevant lethal disease states.
The following discoveries were all made by PCF-supported scientists:
Genetics – William B. Issacs, PhD, at Johns Hopkins discovered a blood test that detects DNA changes in five chromosome regions that can predict a ten-times higher lifetime risk for prostate cancer. Once confirmed in broader, diverse populations, a simple saliva test could provide a useful life-predictive test for men with a family of prostate cancer.
Targeted Therapies – Eugene Kwon, MD, at the Mayo Clinic identified three new “brakes” in the male immune system that prevents a patient’s immune system from seeing and attacking prostate cancer. The “brake” (B7H3) may be released using new therapeutic agents that could block the function of B7H3 For patients, new drugs to awaken the proper immune response can now be developed.
Targeted Therapies – Arul Chinnaiyan, MD, PhD, and his colleagues at the University of Michigan discovered a chromosomal translocation and fusion of two unrelated genes (TMPRSS2 and ERG) that is unique to prostate cancer. The team is now developing a system to screen hundreds of molecules that might inhibit activity of ERG and prevent it from binding to TMPRSS2 to slow or stop the progression of prostate cancer. Further, because the fusion of these genes is easily detected and unique to prostate cancer, they are good targets for cancer-killing therapies that could kill prostate cancer cells without damaging healthy cells. For patients, the fusion is a landmark molecular finding that can guide precisely which treatments are best matched for them.
Biomarkers – A key genetic change in prostate cancer is the loss of the PTEN gene that may be involved with metastasis. Charles Sawyers, MD, at UCLA and Memorial Sloan-Kettering Cancer Center, discovered a marker in the blood known as Insulin Growth Factor Binding Protein 2. For patients, this could mean earlier diagnosis of disease activity in the bone (compared to bone scans) using a test that employs a proteomics-based technology to detect microscopic cancer growth through blood analysis.
Nutrition – William Nelson, MD, PhD, at Johns Hopkins identified that a major carcinogen (PHip) found in charred, grilled meats appears to accumulate in the area of the prostate that later develops prostate cancer, but that does not accumulate in other regions of the prostate for reasons still to be determined. Ultimately, further research into why PhiPs accumulate in the prostate may help reduce the incidence of prostate cancer and change dietary recommendations to protect men from prostate cancer.
Androgen Receptors – Peter Nelson, MD, and Elahe Mostagel, MD, PhD, at the Fred Hutchinson Cancer Research Center and the University of Washington, determined that not all patients undergoing hormone therapy may achieve full suppression of androgens. Some tumor microenvironments may create survival testosterone chemically from normal cholesterol. The development of new therapeutic agents to block this action could benefit more than 100,000 U.S. men whose tumors are resistant to current hormonal therapies.
Nutrition – Oxidation damages biological molecules and is believed to be partially responsible of the initiation and progression of cancer. Consumption of foods rich in antioxidants may counteract oxidative stress and provide beneficial effects against cancer. David Heber, MD, PhD, at UCLA, demonstrated that several large antioxidant molecules called polyphenols exist in strawberries. Whole strawberry extract and the individual polyphenols isolated from strawberry extracts slowed proliferation of prostate, oral and colon cancer cell cultures. Response to purified polyphenols is dose dependant and related to the antioxidant activity of each compound. A new science that can best determine which compounds and supplements should be incorporated into the diet is emerging for patients.
Drug Development – The PCF Prostate Cancer Models Working Group comprised of 13 former PCF competitive award recipients from 12 institutions published State of the Science on Current Research Models in Prostate Cancer. This effort was conducted as a public service and provides a comprehensive point of reference for testing new drugs. Underscoring the PCF’s support of ahead of the curve science, many of the new models forwarded by the team will be incorporated into drug and diagnostics development by biotechnology and pharmaceutical industry and new scientists working on prostate cancer.