Master Regulators Underlying Tumor-Microenvironment Interactions in Metastatic Prostate Cancer

The androgen receptor (AR) is the primary driver and main therapeutic target in advanced prostate cancer. However, resistance to anti-androgen therapy is inevitable, and current therapeutic options for AR-therapy resistant disease have only a limited impact on patient survival. Identification of master regulator (MR) proteins that drive aggressive prostate cancer, as well as drugs that can specifically target these MRs, is critical for advancing treatment and extending the lives of patients. Califano and his laboratory have developed novel algorithms to tease out MR’s using gene expression profiling data. Drs. Michael Shen and Cory Abate-Shen, along with the team’s young investigator Dr. Cambuli, are using single-cell analyses to investigate MR proteins specific to the immune and stromal components of the tumor microenvironment (TME), while Dr. Loda will perform state-of-the-art imaging of the MR proteins to understand their role in cancer cells. The investigators will test drugs that can specifically target these MRs as a precision oncology based approach to treatment. A proof-of-concept precision medicine clinical trial will be performed with mCRPC patients in the Bronx VA hospital, under the direction of Drs. Drake, Bates, and Fojo. Single-cell analysis of patient tumor biopsies will be performed to identify TME-based master regulators that can be targeted with existing drugs. Predicted treatment regimens will be prioritized based on expected impact, agent availability, and activity in parallel studies in patient-derived tumor cultures and xenografts. A final treatment regimen will be selected by the treating physician in conference with the study team. Master regulators that drive prostate tumor/microenvironment interactions will be identified using gene expression data from single cells isolated from tumors, and validated in preclinical models. The types of tumor/microenvironment cells that express master-regulators driving prostate cancer progression, their location within cells, and their effects on the tumor microenvironment, will be determined in experimental models. If successful, this project will identify novel prostate cancer drivers from the tumor microenvironment, and validate these as therapeutic targets in a precision medicine clinical trial. What this means to patients: Advanced prostate cancer is currently incurable and new treatment strategies are urgently needed. This team will develop a precision medicine platform to identify and validate individualized treatments that target novel prostate cancer drivers in the tumor microenvironment.