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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23CA102544-05
Application #
7278236
Study Section
Subcommittee G - Education (NCI)
Program Officer
Gorelic, Lester S
Project Start
2003-09-01
Project End
2009-08-31
Budget Start
2007-09-07
Budget End
2009-08-31
Support Year
5
Fiscal Year
2007
Total Cost
$134,703
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Vallabhajosula, Shankar; Nikolopoulou, Anastasia; Jhanwar, Yuliya S et al. (2016) Radioimmunotherapy of Metastatic Prostate Cancer with ┬╣??Lu-DOTAhuJ591 Anti Prostate Specific Membrane Antigen Specific Monoclonal Antibody. Curr Radiopharm 9:44-53
Tagawa, Scott T; Milowsky, Matthew I; Morris, Michael et al. (2013) Phase II study of Lutetium-177-labeled anti-prostate-specific membrane antigen monoclonal antibody J591 for metastatic castration-resistant prostate cancer. Clin Cancer Res 19:5182-91
Autio, Karen A; Pandit-Taskar, Neeta; Carrasquillo, Jorge A et al. (2013) Repetitively dosed docetaxel and ┬╣?┬│samarium-EDTMP as an antitumor strategy for metastatic castration-resistant prostate cancer. Cancer 119:3186-94
Dennis, Elizabeth R; Jia, Xiaoyu; Mezheritskiy, Irina S et al. (2012) Bone scan index: a quantitative treatment response biomarker for castration-resistant metastatic prostate cancer. J Clin Oncol 30:519-24
Antonarakis, Emmanuel S; Carducci, Michael A; Eisenberger, Mario A et al. (2012) Phase I rapid dose-escalation study of AGS-1C4D4, a human anti-PSCA (prostate stem cell antigen) monoclonal antibody, in patients with castration-resistant prostate cancer: a PCCTC trial. Cancer Chemother Pharmacol 69:763-71
Morris, M J; Eisenberger, M A; Pili, R et al. (2012) A phase I/IIA study of AGS-PSCA for castration-resistant prostate cancer. Ann Oncol 23:2714-9
Beattie, Bradley J; Smith-Jones, Peter M; Jhanwar, Yuliya S et al. (2010) Pharmacokinetic assessment of the uptake of 16beta-18F-fluoro-5alpha-dihydrotestosterone (FDHT) in prostate tumors as measured by PET. J Nucl Med 51:183-92
Morris, Michael J; Huang, Daisy; Kelly, William K et al. (2009) Phase 1 trial of high-dose exogenous testosterone in patients with castration-resistant metastatic prostate cancer. Eur Urol 56:237-44
Morris, Michael J; Pandit-Taskar, Neeta; Carrasquillo, Jorge et al. (2009) Phase I study of samarium-153 lexidronam with docetaxel in castration-resistant metastatic prostate cancer. J Clin Oncol 27:2436-42
Pandit-Taskar, Neeta; O'Donoghue, Joseph A; Morris, Michael J et al. (2008) Antibody mass escalation study in patients with castration-resistant prostate cancer using 111In-J591: lesion detectability and dosimetric projections for 90Y radioimmunotherapy. J Nucl Med 49:1066-74

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