Effective treatments for advanced prostate cancer are urgently needed. The overarching theme of this consortium award is the identification of entirely new therapeutic targets and concepts for treating prostate cancer that has spread (metastasized). The overarching theme of this Department of Defense Prostate Cancer Consortium Award addresses a critical and national issue in prostate cancer research. We do not have treatment that extends overall patient survival with metastatic, hormone refractory prostate cancer. The specific theme of this proposal is to develop new treatment ideas, based on understanding on the pathways that lead prostate cancer cells to spread to the bone (metastasize). We intend to study new targets involved in human skeletal and visceral metastasis of hormone refractory prostate cancer. This Consortium intends to create a pipeline of new ideas for prognosis and new candidate experimental agents. Our project management plan is based on principles from the Manhattan Project led by General Leslie Grove and Dr. J. Robert Oppenheimer and on the use of web-based video-conferencing and online videostreaming data sharing technologies. More than one atomic bomb prototype was designed by separate teams, which were allowed creative latitude from a coordinating center in New Mexico.

The components of our ¿Manhattan Project for Prostate Cancer¿ are five Synergy Teams. Synergy Teams will be composed of three or more Consortium Investigators (CIs) and all their laboratory members. These investigators are all established senior and leading researchers in prostate cancer at 11 major US academic centers of biomedical research. Synergy Team 1 will study the biology and new models of bone metastases. In Project A, molecular pathways in bone metastasis will be identified. In Project B, new models of how prostate cancer bone metastases occur will be assessed. Synergy Team 2 will be evaluating new approaches to kill specifically prostate cancer cells with gene therapy. Project C will evaluate how to improve gene therapy by improving the ability of gene therapy approaches to attack cancer and not kill normal cells. Project D will test new concepts in gene therapy by combining it with radiation therapy and chemotherapy approaches. Synergy Team 3 will assess discoveries made by all five Synergy Teams to develop written clinical trial protocols for peer review and thus accelerate early clinical investigation to funding sources in the federal or foundation or pharmaceutical sectors. This will be accomplished in Project E. Synergy Team 3 will not conduct clinical trials or enroll human subjects in this grant proposal. Synergy Team 4 will study different signal pathways that may be Achilles heel¿s for prostate cancer if they are disrupted with new medicines. In Project F, cholesterol-dependent cell survival mechanisms will be evaluated as a new target that allows prostate cancer cells to survive. In Project G, key pathways from cell surface receptors that allow prostate cancers to grow and divide will be studied to be specifically disrupted with a new class of agents called ansamycins. In Project H, apoptosis signal defects involved in recurrent prostate cancer that are driven by a gene called Ras will be analyzed. Synergy Team 5 will identify new genes that are implicated in the spread and survival of prostate cancer using three tissue banks of biopsies given by patients who gave informed consent. Each Synergy Team has a Captain who is responsible for the prosecution of research within the team and in integrating team research activity with the administrative core of the consortium. In racing to build the atomic bomb before Hitler, American scientists came together in Los Alamos, New Mexico and gave up their egos to work together. Their leader was J. Robert Oppenheimer who said, ¿None of us is as smart as all of us.¿ This is our philosophy for this Department of Defense ¿Manhattan Project¿ on Prostate Cancer.