Targeting the Aberrant Androgen Receptor in Advanced Treatment Resistant Prostate Cancer.

摘要

Purpose: We hypothesize that: i) therapeutic agents that target AR-Vs as well as AR-FL will effectively disrupt the lethal mitotic phenotype; ii) the AR-V-driven transcriptome can provide biomarkers to identify patients at risk for progression and death from CRPC iii) elucidation of mechanism(s) by which AR-Vs activate a lethal phenotype will direct the design of future therapies for CRPC, particularly peptidomimetics that target specific AR-Vs or key AR interacting cofactors. Scope: Aim 1. Instigate clinical trials to assess whether two novel AR-NTD targeting agents (AT13387 or T6) can reverse resistance to abiraterone and/or MDV3100). Aim 2. Evaluate if expression of specific AR-Vs or transcriptomes can serve as predictive and prognostic biomarkers for disease progression. Aim 3. Identify the key effectors and regulators of signaling by AR-Vs in CRPC and assess their potential as biomarkers and therapeutic targets. Progress: Task 1. Administrative organization and approvals have been completed. Task 2. Phase 1 HSP90 resourcinol study completed. Tissue evaluation ongoing. Task 3. Peptidomimetic development underway. Task 4. Materials have been transferred from clinical studies various sites. AR-V relationship to clinical outcomes underway. Task 5. New binding partners identified. Task 6. Genomic mechanisms underlying CRPC-associated AR signaling in prostate cancer has begun. VCaP studies nearing completion. Significance: Unique signaling components of the AR-Vs have been identified as well as coregulators.