microRNA Biomarkers to Generate Sensitivity to Abiraterone-Resistant Prostate Cancer

Abstract : We plan to develop a combination therapeutic approach, employing Abiraterone (Abi) plus RNA therapy. For this, we will use an aptamer specific for PSMA (aptPSMA) to specifically target CRPC cells. The affinity and high specificity of aptPSMA for binding human CRPC cells expressing PSMA has already been reported, as has its utility as a drug delivery system for siRNAs. However, it has not been used to deliver pre-miRNA to cells. Identification of Abi-R markers is important for designing therapeutic interventions sensitizing PCas to combination therapies and for prognostic applications to monitor and predict for disease relapse (Abi-R). Additionally, we propose to use patient derived PCa xenograft animal model (PCa-PDX mice) to identify differentially expressed microRNA (miRNA) on castration and Abi dependent tumor regression followed by regrowth/relapse. Our central hypothesis is that changes in miRNA expression underlie Abi-R mechanisms and that PCa-PDX mice will be excellent surrogates to identify markers for Abi-R. We further postulate that RNA therapy(restoring or targeting miRNA) should increase sensitivity of Abi-R tumors, allowing us to prolong treatments, and hence the life of a patient. Our Aims: (1) To develop RNA aptamer therapy. We will test 8 of the recently identified Abi regulated miRNAs for therapeutic utility in vitro. We will design an aptPSMA-pre-miRNA therapeutic delivery vehicle for CRPC-tissue specific delivery. The best miRNA will be used for in vivo studies (2) To generate Abi-R PDX mice and identify the differentially expressed miRNA.