Novel mechanisms of resistance to antiandrogen therapies

Enzalutamide获批用于治疗转移性去势抵抗性前列腺癌（CRPC）。 尽管这些进展提供了生存增益，但仍然没有治愈CRPC的方法。抗 Enzalutamide频繁发生，其机制尚不完全清楚。因此，解剖 负责CRPC耐药性的特异性适应性/耐药途径，并确定新的 针对这些途径的策略将极大地影响CRPC男性患者的护理。Lin28，RNA 结合蛋白，作为致癌基因诱导细胞增殖和转化。Lin 28抑制let-7， 一种参与抑制雄激素信号传导的miRNA。我们的初步数据表明，Lin 28促进了 去势抵抗性前列腺癌进展并与雄激素消融抵抗相关 治疗Lin 28在前列腺癌中上调，其表达与晚期肿瘤阶段相关。 总之，这些研究强调了Lin 28在促进前列腺癌进展中的重要性， 对恩杂鲁胺耐药，表明靶向Lin 28可能为 前列腺癌该提案将确定Lin 28在Enzalutamide耐药中的作用，并探索 靶向Lin 28克服抗性的潜力。该提案的具体目标是：1.审查 Lin 28在Enzalutamide耐药性发展中的作用。2.确定分子机制 潜在的Lin 28介导的Enzalutamide耐药性。3.评价靶向Lin 28以克服耐药性 Enzalutamide治疗。拟议的研究将确定和表征一种新的耐药性 涉及Lin 28的机制，并评价靶向Lin 28以克服对Enzalutamide治疗的耐药性。

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.