RATIONAL DESIGN OF PROSTATE-SPECIFIC MEMBRANE ANTIGEN DNA VACCINES

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DESCRIPTION (provided by applicant): The MSKCC SPORE in Prostate Cancer, initially funded in 2001, focused on four broad translational research goals: (1) to develop better predictive models of prognosis for localized prostate cancer incorporating validated molecular markers to improve treatment selection; (2) to identify critical molecular and genetic mechanisms of prostate carcinogenesis, progression, and metastasis; (3) to develop PSMA- targeted DMA vaccines for men with rising PSA after local therapy; and (4) to develop new mechanism- based drugs for castrate-resistant metastatic cancers. With strong support from the SPORE and our institution, we have made considerable progress. We have completed a long-term study of watchful waiting in a large British cohort and have collected diagnostic biopsy specimens as tissue microarrays for marker analyses. We have created more than a dozen new animal models of prostate cancer that mimic the human disease, and identified and validated predictive molecular markers. We have documented the efficacy of a PSMA DNA vaccine in a phase 1 clinical trial. And we have demonstrated that Hsp90 targeted therapy with ansamycin degrades the androgen receptor and is active against castrate metastatic prostate cancer. We now have in place an experienced, productive multidisciplinary team of investigators committed to translational research in prostate cancer, a large patient population amenable to participation in clinical trials, and superb infrastructure to support such trials. With a large cadre of scientists exploring the biology of prostate cancer and developing new therapeutic strategies, we have a healthy pipeline of new ideas ripe for investigation as diagnostic and therapeutic interventions. In preparing our SPORE for the next cycle, we have retained the overall objectives and the four major research projects, which function as flexible, multidisciplinary programs where we are able to shift emphasis to the most promising areas of research within the framework of original goals as new information emerges. We have added one new project, Checkpoint Blockade in Immunotherapy of Prostate Cancer, by James Allison, recently recruited here as Chair of Immunology. We will retain five cores (Biospecimen, Biostatistics, Animal Models, Animal Imaging, and Administration) and discontinue the DNA Array Core, replaced by the MSKCC core facility. Career Development has successfully recruited four new translational investigators to our SPORE, and Developmental Research has funded ten pilots with over $1.8 million in additional institutional support, several of which have achieved independent funding. Our investigators collaborate successfully with other SPOREs in Prostate Cancer and institutions and they have been among the leaders in inter-SPORE clinical trials and the pilot National Biorepository Network. With continued support the MSKCC SPORE is well positioned to move novel diagnostic and therapeutic interventions rapidly from the laboratory to the human disease with the goal of reducing morbidity and mortality from prostate cancer.