Therapeutic targeting of PSMA (Prostate-Specific Membrane Antigen) with radiopharmaceuticals has emerged as an option for men with advanced mCRPC, with clear evidence of impact on patient survival. However, predictors of which patients benefit, resistance patterns, underlying mechanisms, and strategies to optimize responses remain open questions. Weill Cornell Medicine has a long history of pioneering PSMA-based diagnostics and therapies. This project will leverage that institutional strength to execute an innovative, first in human clinical trial exploring a novel therapeutic strategy to maximize responses to PSMA-targeting radiopharmaceuticals by increasing the dose delivered directly to the tumor cells using combinatorial targeting. Preclinical studies will define the mechanisms responsible for this phenomenon and establish molecular predictors of sensitivity. In addition, this project will provide proof of principle that dual antibody/small molecule targeting can increase dose delivered to tumors while diminishing toxicity that results from off-target effects and improve patient response (a concept applicable across a variety of cancers), and establish predictors of response to PSMA-targeting therapies. These innovative, highly translational studies will have major near term patient impact, not only within the PCa field, but also broader impact across the entire spectrum of cancers treated with radiopharmaceuticals and other agents with tumor-targeted payloads

Aim 1. Determine the uptake and retention of small molecule ligand (SML) in prostate cancer cells in the presence or absence of anti-PSMA mAb.

Aim 2. Define factors associated with resistance to SML and the ability to overcome resistance with increased dose of radiation