(Project 3) Metastatic castration-resistant prostate cancer (mCRPC) remains an incurable disease for which novel molecular mechanism-based combination therapy strategies are needed. We identified an androgen receptor (AR)- and c-Myb?co-regulated DNA damage response (DDR) gene signature that is highly correlated with castration-resistance, metastasis, and reduced overall survival in mCRPC patients. In this DDR gene signature homologous recombination (HR) DNA repair genes and HR modulator (HRM) genes are highly represented. The relatively large percentage of HR/HRM genes in the DDR gene signature underscores the importance of this group of genes to prostate cancer progression. Our preliminary preclinical studies demonstrated that enzalutamide (ENZ), a 2nd-generation anti-androgen that blocks androgen from binding to the androgen receptor (AR), suppressed the expression of a majority of the HR/HRM genes and synergized with olaparib (OLA), a poly(ADP-ribose) polymerase 1 (PARP1) inhibitor in suppressing prostate cancer growth. Previously, OLA has been associated with synthetic lethality in multiple malignancies with BRCA1/2 or other HR gene deficiencies and its target, PARP1, plays a crucial role in base excision repair (BER) and was reported to function as an AR co-factor. In this project, we propose to test the hypothesis that targeting AR (ENZ) and PARP (OLA) in a ?lead-in? strategy will generate synthetic lethality in mCRPC through ENZ-mediated downregulation of HR/HRM gene activity and OLA-mediated suppression of PARP?s enzymatic activity in BER and PARP?s cofactor role of AR transcriptional activity. The lead-in trial design will allow us to efficiently determine the clinical relevance of our biological findings by linking baseline to sequential modulation of target genes in individual cancers. We will test this hypothesis in three specific aims.
Aim 1. Characterize the HR/HRM gene signature in bone marrow biopsies of men with mCRPC treated with enzalutamide and/or abiraterone, novel inhibitors of androgen signaling.
Aim 2. Further characterize the synergistic potential of and identify predictive biomarkers of response to combination therapies that co-target AR (ENZ) and PARP function (OLA) using preclinical models.
Aim 3. Conduct a clinical trial of treating CRPC patients with ENZ followed by the addition of the PARP inhibitor OLA to achieve greater therapeutic response and to correlate an ENZ-regulated HR/HRM gene signature to the therapeutic responses.
(Project 3) The results of our proposed studies will (1) define a panel of HR/HRM genes that predict clinical response of mCRPC to novel AR-signaling inhibitors and 2ndgeneration anti-androgens; (2) select specific HR/HRM expression-based biomarkers for ENZ, OLA and ENZ+OLA therapy to stratify CRPC patients for maximum benefit in clinical trials; and (3) conduct a clinical trial that will provide greater therapeutic benefit and correlate selected biomarkers to tumor response. Overall, the results of these studies will establish predictive biomarkers and a novel mechanistic framework for the optimization and use of the combination of ENZ and OLA to treat mCRPC.
|Luo, Yong; Azad, Abul Kalam; Karanika, Styliani et al. (2017) Enzalutamide and CXCR7 inhibitor Combination Treatment Suppresses Cell Growth and Angiogenic Signaling in Castration-Resistant Prostate Cancer Models. Int J Cancer :|
|Lin, Song-Chang; Lee, Yu-Chen; Yu, Guoyu et al. (2017) Endothelial-to-Osteoblast Conversion Generates Osteoblastic Metastasis of Prostate Cancer. Dev Cell 41:467-480.e3|
|Gao, Jianjun; Ward, John F; Pettaway, Curtis A et al. (2017) VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer. Nat Med 23:551-555|
|Yu, Kai-Jie; Li, Jeffrey K; Lee, Yu-Chen et al. (2017) Cabozantinib-induced osteoblast secretome promotes survival and migration of metastatic prostate cancer cells in bone. Oncotarget 8:74987-75006|
|Tu, Huakang; Gu, Jian; Meng, Qing H et al. (2017) Low serum testosterone is associated with tumor aggressiveness and poor prognosis in prostate cancer. Oncol Lett 13:1949-1957|
|Gökce, Mehmet I; Wang, Xuemei; Frost, Jacqueline et al. (2017) Informed decision making before prostate-specific antigen screening: Initial results using the American Cancer Society (ACS) Decision Aid (DA) among medically underserved men. Cancer 123:583-591|
|Karanika, Styliani; Karantanos, Theodoros; Li, Likun et al. (2017) Targeting DNA Damage Response in Prostate Cancer by Inhibiting Androgen Receptor-CDC6-ATR-Chk1 Signaling. Cell Rep 18:1970-1981|
|Saha, Achinto; Blando, Jorge; Fernandez, Irina et al. (2016) Linneg Sca-1high CD49fhigh prostate cancer cells derived from the Hi-Myc mouse model are tumor-initiating cells with basal-epithelial characteristics and differentiation potential in vitro and in vivo. Oncotarget 7:25194-207|
|Fong, Eliza L S; Wan, Xinhai; Yang, Jun et al. (2016) A 3D in vitro model of patient-derived prostate cancer xenograft for controlled interrogation of in vivo tumor-stromal interactions. Biomaterials 77:164-72|
|Subudhi, Sumit K; Aparicio, Ana; Gao, Jianjun et al. (2016) Clonal expansion of CD8 T cells in the systemic circulation precedes development of ipilimumab-induced toxicities. Proc Natl Acad Sci U S A 113:11919-11924|
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