Prostate cancer is an androgen driven and dependent disease and AR is highly expressed in PCa cells and directly stimulates their growth and survival. Androgen deprivation therapy (ADT) is the primary therapy for metastatic disease. However, despite a high response rate to ADT the vast majority of patients will progress to castration resistance (CRPC) which is the terminal phase of the disease; metastatic CRPC (mCRPC) is a major cause of morbidity and the second leading cause of cancer mortality in American men, with an estimated 26,730 deaths in 2017. Progression to castration resistance is a function of clonal selection and adaptation via AR dependent and independent mechanisms including AR gene amplification or mutations or alteration in survival pathways bypassing AR. The continued importance of AR signaling in mCRPC is best reflected by the fact that two AR signaling targeted agents, Abiraterone (Abi) and Enzalutamide (Enz), were FDA approved for management of mCRPC based on phase III clinical trials data demonstrating an impact on survival in the pre- and post-docetaxel settings. These treatments are generally well tolerated, however their effect on survival is modest and a significant percentage of patient do not respond or have short duration of response. Therefore, comprehensive understanding of mechanisms of resistance to these agents is critical and therapy personalization to overcome the resistance will have significant clinical impact. Our preliminary analysis revealed C-X-C chemokine receptor 7 (CXCR7), a high-affinity receptor for chemokine ligand CXCL12, among the most up-regulated genes in Enz-resistant derivative of prostate cancer cells. Preliminary studies further suggest that CXCL12-bound CXCR7 activates MAPK/ERK signaling. Concordantly, pERK level is markedly up-regulated in Enz-resistant prostate cancer, the growth of which can be effectively abolished by either CXCR7 depletion or MAPK/ERK inhibition. These findings lead to our hypothesis that CXCR7/MAPK/ERK signaling drives CRPC progression and resistance to AR-targeted therapies and that clinically available MAPK/ERK inhibitors might delay or overcome CRPC drug resistance. To test these hypotheses, we propose three Specific Aims. Aim 1. To analyze CXCR7-MAPK-ERK pathway in PCa models and in mCRPC patient specimens. Aim 2. To determine the functional importance of the CXCR7-MAPK-ERK pathway in CRPC progression and Enz resistance using preclinical models and in the tumor microenvironment using transgenic mice. Aim 3. To test the efficacy of MAPK-ERK inhibitors in overcoming CRPC Enz resistance using preclinical and PDX models and to develop novel CXCR7 antagonists.
|Effective start/end date||12/31/17 → 12/31/22|
- Prostate Cancer Foundation (17CHAL22)
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