(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.

Public Health Relevance

(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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA140388-10
Application #
10005152
Study Section
Special Emphasis Panel (ZCA1)
Project Start
2009-09-02
Project End
2021-08-31
Budget Start
2020-09-01
Budget End
2021-08-31
Support Year
10
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Type
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Yu-Lee, Li-Yuan; Yu, Guoyu; Lee, Yu-Chen et al. (2018) Osteoblast-Secreted Factors Mediate Dormancy of Metastatic Prostate Cancer in the Bone via Activation of the TGF?RIII-p38MAPK-pS249/T252RB Pathway. Cancer Res 78:2911-2924
Luo, Yong; Azad, Abul Kalam; Karanika, Styliani et al. (2018) Enzalutamide and CXCR7 inhibitor combination treatment suppresses cell growth and angiogenic signaling in castration-resistant prostate cancer models. Int J Cancer 142:2163-2174
Soundararajan, Rama; Aparicio, Ana M; Logothetis, Christopher J et al. (2018) Function of Tumor Suppressors in Resistance to Antiandrogen Therapy and Luminal Epithelial Plasticity of Aggressive Variant Neuroendocrine Prostate Cancers. Front Oncol 8:69
Class, Caleb A; Ha, Min Jin; Baladandayuthapani, Veerabhadran et al. (2018) iDINGO-integrative differential network analysis in genomics with Shiny application. Bioinformatics 34:1243-1245
Lin, Song-Chang; Yu-Lee, Li-Yuan; Lin, Sue-Hwa (2018) Osteoblastic Factors in Prostate Cancer Bone Metastasis. Curr Osteoporos Rep 16:642-647
Wang, Hong; Yang, Xu; Liu, Anna et al. (2018) ?-Tocopherol inhibits the development of prostate adenocarcinoma in prostate specific Pten-/- mice. Carcinogenesis 39:158-169
Velazquez-Torres, Guermarie; Shoshan, Einav; Ivan, Cristina et al. (2018) A-to-I miR-378a-3p editing can prevent melanoma progression via regulation of PARVA expression. Nat Commun 9:461
Zanoaga, Oana; Jurj, Ancuta; Raduly, Lajos et al. (2018) Implications of dietary ?-3 and ?-6 polyunsaturated fatty acids in breast cancer. Exp Ther Med 15:1167-1176
Zhang, Wei; Liu, Bo; Wu, Wenhui et al. (2018) Targeting the MYCN-PARP-DNA Damage Response Pathway in Neuroendocrine Prostate Cancer. Clin Cancer Res 24:696-707
Monroig-Bosque, Paloma Del C; Shah, Maitri Y; Fu, Xiao et al. (2018) OncomiR-10b hijacks the small molecule inhibitor linifanib in human cancers. Sci Rep 8:13106

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