Targeting Androgen Receptor and PARP for Synthetic Lethality in CRPC

靶向雄激素受体和 PARP 来实现 CRPC 的综合致死性

• 批准号: 10706700
• 负责人: Timothy Charles Thompson
• 金额: $ 30.91万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-02 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10706700
• 关键词: Administrative Supplement; Androgen Antagonists; Androgen Receptor; Androgen Suppression; Androgens; Base Excision Repairs; Binding; Biological; Biological Markers; Biopsy Specimen; Bone marrow biopsy; Cancer Center; Cancer Patient; Castration; Clinical Trials; Combined Modality Therapy; Conduct Clinical Trials; DNA Damage; DNA Repair Gene; Disease; Down-Regulation; Gene Expression; Generations; Genes; Genetic Transcription; Growth; In Vitro; Individual; Institution; Lead; Link; MYB gene; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Molecular; Neoplasm Metastasis; Patients; Play; Poly(ADP-ribose) Polymerases; Pre-Clinical Model; Receptor Signaling; Reporting; Resistance; Role; Signal Transduction; Testing; Therapeutic; abiraterone; base; brca gene; castration resistant prostate cancer; clinical predictors; clinically relevant; cofactor; cytotoxicity; enzalutamide; genetic signature; homologous recombination; in vivo; inhibitor; men; novel; pre-clinical; preclinical study; predictive marker; prospective; prostate cancer cell; prostate cancer model; prostate cancer progression; response; response biomarker; treatment response; trial design; tumor

PROJECT SUMMARY (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.

项目总结（项目3）