Prostate cancer is the second most common cause of cancer-related deaths in American men. Patients with advanced disease are not curable using standard approaches and suffer the effects of metastatic disease to bone, the primary site of distant spread. The candidate's research to date is based on the approach that prostate cancer can be treated by targeting the unique biologic features that characterize the tumor in each clinical state of the disease's natural history. The specific hypothesis of this grant is that techniques applied to hematologic tumors, such as radioimmunotherapy (RIT), can also be applied to prostate cancer, given that the main reservoir of resistant disease is the bone marrow. The proposed target is prostate specific membrane antigen (PSMA), which is present at all phases of the disease, is minimally expressed in non-prostate tissue, and can be modulated. Preliminary studies to define the properties of unlabeled and yttrium-90 labeled anti-PSMA antibodies, such as huJ591, are now being completed. To implement this research, a comprehensive career development plan for the candidate is proposed, that capitalizes on MSKCC's and the Sponsor's resources and expertise. Three years of didactic courses in clinical trial design and nuclear medicine are planned. Mentoring by experts in the field, such as the Sponsor (Dr. Scher, Chief of GU Oncology), Dr. Larson (Chief, Nuclear Medicine), and members of Radiology, Radiochemistry, Pathology, and Biostatistics are incorporated into the plan. Participation in national/international conferences will allow exposure to other experts and to understand the process of bringing trials to a national stage. Through this training, a research plan based on the following three aims will be executed: (1) To test the hypothesis that repetitively dosed RIT can induce antitumor effects that correlate with tumor absorbed dose. In a phase I trial Y-86-huJ591 (a positron emitter) will be administered with repetitively dosed Y-90-huJ591 (a pure beta emitter) to establish the efficacy, dosimetry, and biodistribution of the yttrium conjugate (2) To test the hypothesis that RIT can be optimized by upregulating target expression and/or enhancing tumor radiosensitivity. In a phase 1/11trial, the yttrium conjugate will be combined with PSMA modulation, and (3) to compare RIT with standard chemotherapy in a phase III trial. The acquisition of these skills combined with the completion of the research plan will allow the candidate to pursue such research independently.
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