Translational research experts rigorously reviewed a wealth of proposals so PCF could provide Challenge Award funds to the top nine teams in less than 100 days. The Challenge Awards-Class of 2008, selected in nine categories of scientific investigation, are:
1. Progression Biomarkers
Lead Investigator: Dr. Daniel Haber, Massachusetts General Hospital
Project Title: Clinical and Biological Insights into Prostate Cancer Derived from the Microfluidic Capture of Circulating Tumor Cells
The discovery of biomarkers that predict disease progression or provide a signal for effectiveness of an experimental medication for prostate cancer is a priority for PCF. These markers will increase the pace of new medication development and signal physicians earlier when prostate cancer is progressing. Dr. Haber, in collaboration with oncologists, biologists and engineers, will refine a system that measures tumor cells in patient blood. Enumeration of these cells provides an early signal of disease progression and will be clinically validated. Molecular evaluation of circulating tumor cells will be performed to better optimize prostate cancer therapy for individuals.
Massachusetts General Hospital research team members: Dr. Richard J. Lee; Dr. Shyamala S. Maheswaran; Dr. Sunitha Nagrath; Dr. Matthew R. Smith; Dr. Mehmet M. Toner.
2. ETS Gene Fusions
Lead Investigators: Dr. Levi A. Garraway, Dana-Farber Cancer Institute, Broad Institute; Dr. Todd R. Golub, Broad Institute of Harvard and MIT; Dr. William C. Hahn, Dana-Farber Cancer Institute, Broad Institute.
Project Title: Discovery of Inhibitors of TMPRSS2/ERG Function in Prostate Cancer
Scientists recently discovered that a specific genetic rearrangement in normal prostate cells leads to the production of cancer promoting factors (ETS factors) and prostate cancer. It is presumed that discovery of medications that block the activity of ETS factors will arrest the growth of prostate cancer. Dr. Golub will apply state-of-the-art genetic biotechnologies in a significant drug discovery effort to target ETS factors produced by prostate cancer cells. Collaborators at the Broad Institute of Harvard and MIT will work with biologists and oncologists at the Dana-Farber Cancer Institute and Harvard Medical School to evaluate ETS factor inhibitors discovered in this work and ultimately develop an experimental medication for prostate cancer patients.
3. Intracrine Androgens and Androgen Receptor Signaling
Lead Investigators: Dr. Steven P. Balk, Beth Israel Deaconess Medical Center; Dr. Philip W. Kantoff, Dana-Farber Cancer Institute; Dr. Peter S. Nelson, Fred Hutchinson Cancer Research Center, University of Washington
Project Title: Synergistic Targeting of AR and Androgen Metabolism in Prostate Cancer
For advanced prostate cancer patients, the best available treatment is the removal of testosterone hormones (androgens) that drive the growth and progression of prostate cancer. Medications that reduce androgens cause clinical remission invariably followed by disease progression. It is now known that androgens can be produced in tumor tissue, which is one cause for disease progression. Drs. Balk, Kantoff and Nelson will carefully study androgen reduction in tumor tissue from patients treated with a new generation of androgen production inhibitors and determine the mechanism of inhibition. Since it is likely that patients will ultimately become resistant to the new medications, identification of the mechanism of resistance will help identify the next generation of prostate cancer treatments.
Research team members: Dr. Myles A. Brown, Dana-Farber Cancer Institute; Dr. Celestia Higano, University of Washington; Dr. Paul Lange, University of Washington; Dr. Bruce Montgomery, University of Washington; Dr. Elahe Mostaghel, Fred Hutchinson Cancer Center; Dr. Trevor M. Penning, University of Pennsylvania; Dr. Mary-Ellen Taplin, Dana-Farber Cancer Institute.
4. Predictive Preclinical Models
Lead Investigator: Dr. Robert L. Vessella, University of Washington
Project Title: Consortium for the Development and Analysis of Relevant Prostate Cancer Model Systems
Laboratory models that reflect prostate cancer clinical biology are important for investigating new treatments for the disease. Dr. Vessella has organized a national consortium of expert investigators that intend to better characterize existing models of prostate cancer and determine where there are gaps in understanding clinical biology. The deficiencies will be corrected by creation of a new generation of models suitable for preclinical assessment of new, experimental medications for advanced prostate cancer.
Research consortium members: Dr. Norman M. Greenberg, Fred Hutchinson Cancer Research Center, University of Washington; Dr. William C. Hahn, Dana-Farber Cancer Institute; Dr. Peter S. Nelson, Fred Hutchinson Cancer Research Center; Dr. Donna M. Peehl, Stanford University; Dr. Kenneth J. Pienta, University of Michigan Medical School; Dr. Hong Wu, UCLA.
5. Nutrition, Metabolism and Patient Quality of Life
Lead Investigator: Dr. Matthew R. Smith, Massachusetts General Hospital Cancer Center
Project Title: Prevention of Treatment and Disease-Related Morbidity During Androgen Deprivation Therapy: A Multi-Center Proposal
The best available treatment for advanced prostate cancer is the removal of testosterone hormones (androgens) that drive the growth and progression of prostate cancer. However, the medications used to reduce androgen in patients with advanced prostate cancer cause significant secondary illness. Dr. Smith and his U.S./Canada team of investigators plan to study the health consequences of androgen reduction and will determine medical interventions to prevent the negative consequences of treatment. This expert team will determine how to limit obesity, diabetes, bone fractures and heart disease in patients treated for advanced prostate cancer. Exercise, nutrition and new medications will be employed to enhance the health of these patients with advanced prostate cancer.
Research team members: Dr. Stephen J. Freedland, Duke University Medical Center; Dr. Nancy L. Keating, Harvard Medical School; Dr. David M. Nathan, Massachusetts General Hospital; Dr. Michael A. Pollak, McGill University/Jewish General Hospital.
Lead Investigator: Dr. Michael G. Rosenfeld, University of California, San Diego
Project Title: Epigenetic Strategies in Androgen Receptor-Dependent Interchromosomal Networking and Translocation
Epigenetics is a relatively new area of cancer biology that describes genetic regulation which is independent from DNA sequence. Cancer occurs due to both mutation and epigenetic alterations resulting in dysregulation of growth control. Only recently have scientists discovered epigenetic changes in tumor cells that can be controlled with new medicines. Dr. Rosenfeld and his expert team propose the application of a new genetic biotechnology to discover genetic and epigenetic changes resulting in prostate cancer. The overall goal of this work is the discovery of new medications that control prostate cancer when all existing treatments have failed.
Research team members: Dr. Xiang-Dong Fu, University of California, San Diego; Dr. Sheng S. Ding, The Scripps Research Institute.
Lead Investigators: Dr. James Allison, Memorial Sloan-Kettering Cancer Center and Dr. Padmanee Sharma, M.D. Anderson Cancer Center
Project Title: CTLA-4 Blockade in Therapy of Prostate Cancer: Therapeutic Mechanisms and New Directions
Immunotherapy is a treatment for cancer that involves directing a patient’s immune response against their cancer to cause elimination of the tumor. A variety of immunotherapeutic strategies for the treatment of prostate cancer are under development. There is a significant need for discovery of blood markers that will herald an anti-tumor response as well as warn of an impending adverse event due to the therapy. Drs. Sharma and Allison are performing clinical evaluation of advanced immunotherapies. They plan to perform a rigorous molecular analysis of the patient response to immunotherapy for treatment of prostate cancer. The goal is to use these findings to develop more effective and safer immunotherapeutic treatments for prostate cancer.
Research team member: Dr. Neal R. Rosen, Memorial Sloan-Kettering Cancer Center.
8. Prostate Cancer Stem Cells
Lead Investigator: Dr. Owen N. Witte, UCLA
Project Title: Defining Targets and Biomarkers in Prostate Cancer Stem Cells: New Therapeutic Opportunities
Cancer stem cells are an elusive, small subpopulation of tumor cells that are not only resistant to therapy but also repopulate a solid tumor after most tumor cells are killed by a therapy. Understanding the biology of cancer stem cells and targeting their elimination is a priority in cancer research. Dr. Witte and his team at UCLA and the Salk Institute of Biological Studies are world leading experts in cancer stem cell biology. This team will now direct their expertise toward studies of prostate cancer stem cells. Application of new genetic biotechnologies will better define this critical tumor cell population and will reveal therapeutic targets.
Research team members: Dr. Pei-Yu E. Chiou, UCLA; Dr. Isla P. Garraway, UCLA; Dr. Michael A. Teitell, UCLA; Dr. Hong Wu, UCLA; Dr. Inder M. Verma, The Salk Institute.
9. Androgen Receptor Signaling Targeted Therapies
Lead Investigator: Dr. Howard Scher, Memorial Sloan-Kettering Cancer Center
Project Title: Prostate Cancer Targeted Therapies Directed to the Androgen-Receptor Signaling Axis as a Model for Drug Development
Activation of the androgen receptor signaling axis (a network of proteins that respond to androgen stimulus) is responsible for prostate cancer growth and survival. Although there are several anti-androgens available many patients experience remission followed by resistance. Dr. Scher and his team are testing new anti-androgen agents, MDV3100 and Abiraterone, in the laboratory and the clinic to determine combinations of targeted agents likely to have potent anticancer effects. This Challenge Award team will also identify whether circulating tumor cell (CTC; rogue cancer cells that have broken off of the tumor and entered the bloodstream) enumeration and prostate cancer specific PET imaging can predict response to these new agents. Another goal is to develop mouse models of MDV-3100 resistance to understand how patients may become resistant to this medicine. The group plans to test other novel targeted therapies in combination with MDV-3100 and Abiraterone to enhance anti-cancer effects and improve overall survival for patients with advanced prostate cancer.
Research team members: Dr. Charles Sawyers; Memorial Sloan-Kettering Cancer Center, Dr. Neal Rosen; Memorial Sloan-Kettering Cancer Center, and Dr. Steve Larson; Memorial Sloan-Kettering Cancer Center.