BLR&D Research Career Scientist Award

BLR

• 批准号: 10454105
• 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: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10454105
• 关键词: Ablation; Androgen Antagonists; Androgen Receptor; Androgens; Award; 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; Research; Resistance; Resistance development; Role; Scientist; Signal Transduction; Small Interfering RNA; System; Technology; Testing; Tumor stage; abiraterone; androgen deprivation therapy; career; 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.

恩扎拉胺被批准用于治疗转移性cast割前列腺癌（CRPC）。 尽管这些进步可以带来生存的增长，但CRPC仍然无法治愈。抵抗 enzalutamide频繁发生，并且该机制不完全理解。因此，解剖 特定的自适应/抗性途径，负责CRPC中的耐药性并识别新颖的途径 针对这些途径的策略将极大地影响CRPC男性的护理。 lin28，一个RNA 结合蛋白充当癌基因诱导细胞增殖和转化。 lin28抑制let-7， 参与抑制雄激素信号的miRNA。我们的初步数据表明LIN28促进 抑制前列腺癌的进展，与对雄激素消融的抗性有关 治疗。 Lin28在前列腺癌中上调，其表达与晚期肿瘤阶段相关。 这些研究共同强调了LIN28在促进前列腺癌的进展和 对恩扎拉胺的耐药性，表明靶向Lin28可能会为新颖的治疗机会提供 前列腺癌。该提案将确定LIN28在抵抗Enzalutamide中的作用，并探索 靶向LIN28以克服电阻的潜力。该提案的具体目的是：1。 LIN28在对恩扎拉胺抗性发展中的作用。 2。确定分子机制 LIN28介导的基础对恩扎拉胺的抗性。 3。评估靶向LIN28以克服电阻 进行enzalutamide治疗。拟议的研究将识别并表征新的阻力 涉及LIN28并评估靶向LIN28以克服对Enzalutamide治疗的抗性的机制。