Novel mechanisms of resistance to antiandrogen therapies

抗雄激素疗法耐药的新机制

• 批准号: 10570826
• 负责人: Allen C Gao
• 金额: --
• 依托单位: VA NORTHERN CALIFORNIA HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10570826
• 关键词: Ablation; Androgen Antagonists; Androgen Receptor; Androgens; Antiandrogen Therapy; Biological; Biomedical Engineering; CWR22Rv1; Caring; Cell Culture Techniques; Cell Proliferation; Cells; Data; Drug resistance; Human; In Vitro; Interleukin-6; LNCaP; Length; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; MicroRNAs; Molecular; Oncogenes; Oncogenic; Pathway interactions; Patients; Play; Production; Proteins; RNA; RNA Splicing; RNA-Binding Proteins; Relapse; Resistance; Resistance development; Role; Signal Transduction; Small Interfering RNA; System; Technology; Testing; Tumor stage; abiraterone; androgen deprivation therapy; castration resistant prostate cancer; cell growth; cell transformation; docetaxel; enzalutamide; improved; in vivo; knock-down; male; men; mortality; new technology; next generation; novel; novel strategies; novel therapeutics; overexpression; prostate cancer cell; prostate cancer progression; resistance mechanism; response; targeted treatment; therapy resistant; tumor growth; tumor xenograft

Enzalutamide was approved for the treatment of metastatic castration resistant prostate cancer (CRPC). Despite these advances that provide survival gains, there is still no cure for CRPC. Resistance to enzalutamide occurs frequently and the mechanisms are incompletely understood. Hence, dissecting the specific adaptive/resistant pathways that are responsible for drug resistance in CRPC and identifying novel strategies targeting these pathways will dramatically impact the care of men with CRPC. Lin28, a RNA binding protein, acts as an oncogene inducing cell proliferation and transformation. Lin28 suppresses let-7, a miRNA involved in suppressing androgen signaling. Our preliminary data suggest that Lin28 promotes castration resistant prostate cancer progression and is associated with resistance to androgen ablation treatment. Lin28 is upregulated in prostate cancer and its expression correlates with advanced tumor stage. Together, these studies underscore the importance of Lin28 in promoting prostate cancer progression and resistance to enzalutamide, suggesting that targeting Lin28 may provide novel therapeutic opportunities for prostate cancer. This proposal will determine the roles of Lin28 in resistance to enzalutamide, and explore the potential of targeting Lin28 to overcome resistance. The specific aims of this proposal are: 1. Examine the roles of Lin28 in the development of resistance to enzalutamide. 2. Determine molecular mechanisms underlying Lin28-mediated resistance to enzalutamide. 3. Evaluate targeting Lin28 to overcome resistance to enzalutamide treatment. The proposed studies will identify and characterize a novel resistance mechanism involving Lin28 and evaluate targeting Lin28 to overcome resistance to enzalutamide treatment.

恩杂鲁胺被批准用于治疗转移性去势抵抗性前列腺癌（CRPC）。