Testing ATAD2 as a new therapeutic target for advanced prostate cancer

PROJECT SUMMARY/ABSTRACT Prostate cancer is the second leading cause of male cancer death. Advanced prostate cancer, whether present at the time of diagnosis or arising after treatment of localized disease, responds to androgen deprivation, but invariably fails and recurs as castration-resistant prostate cancer (CRPC) which is the main cause of prostate cancer-associated mortality. Heavily treated tumors, particularly those treated with secondary hormone therapies, frequently acquire a neuroendocrine phenotype (NEPC), which currently accounts for 15-20% of CRPC. NEPC is commonly characterized by expression of neuroendocrine markers, an aggressive clinical course, and downregulation or loss of androgen receptor (AR) that diminishes responsiveness to androgen deprivation therapies, making it the most lethal and currently incurable subset of prostate cancer. Thus, there is an urgent unmet need to define new therapeutic strategies for adeno-CRPC and NEPC. Our recent studies identified ATAD2 as an up-regulated druggable protein in treatment-induced NEPC. Moreover, we demonstrated that ATAD2 inhibitors dramatically suppress NEPC cell and tumor growth. The goals of the study are to test the therapeutic potential of ATAD2 inhibitor alone or in combination therapy settings in pre-clinical models of adeno-CRPC and NEPC and define new mechanisms through which ATAD2 regulates prostate tumorigenesis. The goal of this proposal is based on strong preliminary results. We propose to use cell line models of adeno-CRPC and NEPC as well as patient-derived xenografts (PDXs) of adeno-CRPC and NEPC to test the proposed combination therapies in pre-clinical settings. The aims of the proposed project are: Specific Aim 1. Test the levels of ATAD2 in a large cohort of clinical specimens. Specific Aim 2. Investigate the functional role of ATAD2 in advanced prostate cancer and define the molecular mechanisms through which ATAD2 contributes to prostate tumorigenesis and NEPC. Specific Aim 3. Test the therapeutic potential of ATAD2 inhibitors alone and in combination with therapies used as a standard of care for prostate cancer in adeno-CRPC and NEPC growth and metastasis.