Discovery 1: A new class of drugs is being studied for its ability to prevent intratumoral androgen production by inhibiting the activity of an enzyme named lyase – a molecule involved in the synthesis of testosterone from precursor cholesterol. This discovery explains, in part, how prostate cancer cells might survive and proliferate after standard hormonal therapy fails.  Three new, distinct, lyase-inhibiting drugs are being developed simultaneously. One of these new targeted medicines, called abiraterone, is currently being tested in the United Kingdom as well as in the United States through the PCF Clinical Trials Consortium. To date, trials with abiraterone have demonstrated significant remissions in more than 40% of men with advanced prostate cancer that is resistant to hormone therapy. Larger clinical trials are planned in 2008 based on the positive findings reported at the 2007 PCF Scientific Retreat.

Implication of Discovery 1: A new "druggable" pathway has been discovered to treat prostate cancers when they cease to respond to currently available hormone therapies. However, additional research effort is needed to identify patients that will optimally respond to lyase inhibitory therapy.

Discovery 2: Prostate cancer is a disease of "chromosomal fusion." A chromosomal fusion results when DNA from one location moves to another location, and fuses to the new spot. This change in the DNA code causes abnormal proteins to be produced, and ultimately leads to the growth of cancer. At least on the level of DNA, this makes prostate cancer unexpectedly similar to some blood cancers, such as chronic myeloid leukemia, which is also characterized by a unique chromosomal fusion. This landmark finding, originally made with PCF support at the University of Michigan, was subsequently confirmed at the Memorial Sloan-Kettering Cancer Center, The Johns Hopkins University, and Harvard University, as well as at other centers in the UK and Holland. All of these centers, working in concert, have confirmed that the fusion occurs commonly at the very onset of prostate cancer, serving as an initial "on" switch for its development, and can be detected on biopsy.

Implications of Discovery 2: With the chromosomal fusion "on" switch identified in prostate cancer, it might now be possible to analyze urine and blood for the tell-tale chromosomal fusions specific for prostate cancer -- and find cancer years before a rise in PSA or abnormal prostate exam. Furthermore, as demonstrated in other areas of oncology, it is possible to design and develop specific targeted medicines against chromosomal fusions. The FDA-approved drug Gleevec is a drug specifically targeting the chromosomal fusion in chronic myeloid leukemia The possibility of developing a prostate cancer "Gleevec" to turn off the unique prostate "on" switch -- inconceivable prior to the University of Michigan discovery -- is now a high priority idea to reduce prostate cancer deaths. The PCF is already funding efforts at several centers to determine whether highly specific drugs against the prostate cancer chromosomal fusion could be designed; these efforts are fostering collaborations among chemists, computer scientists, prostate cancer molecular biologists, and prostate cancer biologists all working toward this important goal.

Discovery 3: Specialized antibodies can stimulate a prostate cancer patient's immune system to fight against his disease. Evidence was presented by PCF-funded researchers in multiple centers in the US and in Holland that clinical remissions in advanced prostate cancer can be achieved using a new antibody therapy called anti-CTLA4 (ipilimumab). However, some patients experienced significant side effects, and further research is underway to evaluate the best dose of anti-CTLA4 antibody. Of note, investigators found that combining the anti-CTLA4 antibody with a prostate cancer vaccine works better in experimental animal models of hormone resistant prostate cancer than when using either treatment alone. Thus, the clinical combination of anti-CTLA4 antibody and prostate cancer vaccines such as GVAX are being tested in Holland. The first human of the combination showed declines in PSA, reduction in the presence of metastatic lymph nodes, and regression of some bone metastases. More Dutch patients are being treated with the combination of anti-CTLA4 antibody and prostate cancer vaccines, and additional combinations of agents with anti-CTLA4 are planned for US clinical trials in 2008. These early, but encouraging findings are the product of 12 years of funding by the PCF on different molecular approaches designed to activate a patient's immune system to attack and destroy his prostate cancer.
 
Implication of Discovery 3: Several large clinical trials underway in the US through the PCF Clinical Trials Consortium are designed to evaluate further the safety of anti-CTLA4 antibody immunotherapy. These immunotherapy trials will provide important data on how to minimize the side effects of treatment, and will determine the frequency and durability of remissions. Laboratory data suggest that anti-CTLA4 antibody might be more effective when used in combination with radiation therapy, while early data from the MD Anderson Cancer Center suggest that it might be possible to use a simple blood test to determine which patients are activating their immune systems and are going to benefit.

Discovery 4: Prostate cancer is a disease of "epigenetic changes," in which normally "good genes" that suppress growth and metastasis are turned off, and "bad genes" that drive growth and metastasis are turned on. These genes are turned on or off by a process called methylation; changes in more than 60 genes involved in prostate cancer growth and development have been reported to date.
 
Implication of Discovery 4: New research insights in epigenetics in prostate cancer funded by the PCF have identified new possibilities for the design of drugs against methylation changes. Although widespread genetic changes have been implicated from these epigenetic changes, methyltransferase enzymes have been identified as specific vulnerable points for prostate cancer cells  Treatment with new "anti-epigenetics" medicines could revert the cancer cell back toward a more normal state of slow growth, or even kill the cancer cell and prevent its spread.

 
Discovery 5: Patient metabolism and nutrition are critical factors in prostate cancer initiation and tumor growth. Inflammation and inflammatory cells inside the prostate are involved in driving prostate cancer growth. Similarly, inflammation around metastatic prostate cancers may fuel their growth as well. Diets that provide less "fuel" for inflammatory cells in the prostate and that reduce the presence of pro-inflammatory free oxygen radicals, appear to increase life expectancy in prostate cancer animal models. Further PCF research is underway on the ideal "anti-inflammatory diet" -- with a focus on developing specific recommendations for men who have been diagnosed with prostate cancer, as well as recommendations for families with histories of prostate cancer who want to lower their risk of developing the disease.

In metabolism research, more evidence exists that specific hormones released by fat cells might promote prostate cancer cell survival. In fact, abdominal fat might be a particularly large source of these growth factors for cancer cells. Fat, it turns out, is not just insulation, but can work as a hormone-producing organ. Furthermore, food preparation could affect lifetime prostate cancer risk. A major dietary cancer-causing chemical (carcinogen) called PhiP accumulates in the prostate upon ingestion of charred red meats, fish, or chicken. Of interest to epidemiologists are the far lower rates of prostate cancer in Asia, and the relative absence of charred meat in Asia, compared to American and European cuisine.

Implications of Discovery 5: Further research and research support is needed on scientific metabolic parameters and dietary recommendations for each prostate cancer patient. Research on fat cells, lifestyle choices, and exercise programs are all now warranted. Evidence in animal models suggests that PhiPs need to be reduced or eliminated from the human diet by preparation of meat that does not involve charring.

Discovery 6: Five new markers of prostate cancer disease activity might help speed testing of more effective drugs against advanced prostate cancer. Additional tests beyond the PSA are urgently needed to help patients and their doctors determine earlier whether a treatment is working. PCF is focused on driving forward research on these "progression markers." Three of these new tests in early research and development are testing for the EPCA 2 protein, TMPRSS2 chromosomal fusions, and circulating tumor cells. The other two new markers are being tested in the field of diagnostic imaging using advanced PET (positron emission tomography) techniques. Both of the new PET technologies could potentially be more useful than the existing technology of PET in the clinic. The first technology is FLT-PET, which identifies rapid DNA division in fast-growing cells, and appears to be more selective for "lighting up" tumor cells on a scan that are otherwise invisible using current PET technology. The second technology, DHT-PET, labels prostate cancer cells containing the androgen receptor, and therefore "lights up" metastatic prostate cancers on a scan based on the biochemical activity of a pathway that prostate cancer cells are exploiting to survive.

Implications of Discovery 6: All 5 of these new methods of monitoring prostate cancer disease activity need further research to validate their usefulness in the clinic. If any, some, or all are ultimately approved for use by the FDA, they would allow more speedy determinations of whether new anti-prostate cancer medicines are effective.

 
Discovery 7: Biodegradable particles on the nanometer scale can be programmed to carry and deliver anti-cancer drugs to prostate cancers in far more specific ways compared with conventional chemotherapeutic drugs. Nanotechnology enables the design drugs and devices at the scale of 1/100,000th the width of a human hair. Investigators at the Massachusetts Institute of Technology are studying the feasibility of creating "Trojan horses" in the form of engineered biodegradable nano-particles that carry anticancer medicines into prostate cancer cells with far better delivery success compared with current chemotherapeutic drugs. With philanthropic support of David Koch through the PCF, this approach to new advanced prostate cancer treatment received a $5 million research award to accelerate research and development.

Implications of Discovery 7: This technology promises to deliver therapy directly to cancer cells throughout the patient's body but will be inert to normal cells and tissues. This will allow powerful drugs to be delivered systemically, at very high dose, with a greatly reduced probability for the toxic side effects of current chemotherapy. Furthermore, the "therapeutic window" will be widened and higher concentrations of anti-cancer drugs will accumulate in the tumor which in turn will result in greater killing of the malignant target.