PSMA LIGANDS FOR TARGETED CANCER RADIOTHERAPY

DESCRIPTION (provided by applicant): We will determine the feasibility of using a small molecule inhibitor of prostate specific membrane antigen (PSMA) conjugated to a radiotoxin as targeted therapy for prostate cancer (PC). PC is the most commonly diagnosed malignancy in males in the United States, resulting in 31,000 deaths annually. The dipeptidase, PSMA, is the most well-established, prostate-enriched, cell surface protein known. Compared to normal prostate, PSMA levels dramatically rise in PC, and are highest in hormone refractory and metastatic disease. PSMA monoclonal antibodies conjugated to beta-emitters have been found to target PC selectively, and provide tumoricidal efficacy in preclinical and preliminary clinical studies. Small molecule conjugates may offer several therapeutic advantages over antibodies including ease of synthesis and enhanced tumor penetration. In collaboration with John V. Frangioni, M.D., Ph.D., Harvard Medical School, we found that the potent Guilford PSMA inhibitor, GPI18648, conjugated to a near-infrared fluorophor specifically targeted PSMA-expressing cells. We have now synthesized GPI 18648-DOTA-Y, and find that it retains potency as a PSMA ligand, Kd approximately 4 nM. We will characterize GPI 18648-DOTA-(90)Y/111 in PC cell culture and xenograft animal models. Positive results will justify Phase II studies leading to PC clinical trials and commercialization of novel targeted therapeutics for PC.