The role of cholesterol homeostasis in enzalutamide resistance

项目总结 前列腺癌(PC)是全世界男性中最常见的恶性肿瘤，是第二大恶性肿瘤 美国男性癌症死亡原因。一个人一生中开发个人电脑的风险是七分之一。 重要的是，雄激素受体(AR)信号不仅对PC的启动至关重要，而PC最初是 雄激素依赖型，也适用于抗阉割疾病。苯扎鲁胺(ENZ)是第一个也是唯一一个FDA- 批准的第二代AR拮抗剂用于治疗非转移性和转移性 抗去势个人计算机(CRPC)。然而，几乎所有的PC患者都对雄激素剥夺产生了抵抗力。 治疗(ADT)。已经得到充分证实的是，PC向抗阉割生长和 ADT耐药的发生与Akt/mTOR信号的异常激活有关。重要的是 PI3K/Akt/mTOR轴在PC细胞中作为雄激素信号通路的转录整合因子。为 多年来，PC中的胆固醇动态平衡一直是研究的重点之一。始终如一 对胆固醇和PC之间关系的兴趣在很大程度上是由于胆固醇参与了De 新雄激素合成。我们的初步研究表明，主要的胆固醇组分(即低密度脂蛋白、高密度脂蛋白和 极低密度脂蛋白(VLDL)可增强PC细胞Akt/mTOR信号的激活，这与其对ENZ的耐药性相一致。 用Akt/mTOR抑制剂治疗后，成功地恢复了对ENZ的敏感性。基于这些 发现，我们假设除了作为雄激素生物合成的前体外，脂蛋白- 衍生胆固醇可能通过雄激素非依赖性激活促进PC细胞抗去势生长 AKT/mTOR通路。来验证我们的假设并验证靶向胆固醇的治疗价值 PC细胞的动态平衡为了提高ENZ的抗肿瘤效果，我们提出了以下特异性的方法 目的：(1)确定胆固醇稳态在苯扎鲁胺抵抗中的作用；(2)改善 以细胞胆固醇稳态为靶点的苯扎鲁胺抗肿瘤作用。我们预计， 拟议的研究将获得洞察力，为PC的治疗提供新的治疗选择。

PROJECT SUMMARY Prostate cancer (PC) is the most common malignancy among males worldwide, and is the second leading cause of cancer death among men in United States. A man's life-time risk of developing PC is one in seven. Importantly, androgen receptor (AR) signaling is vital not only for the initiation of PC, which is initially androgen-dependent, but also for castration-resistant disease. Enzalutamide (ENZ) is the first and only FDA- approved second-generation AR antagonist used for the treatment of both non-metastatic and metastatic castration-resistant PC (CRPC). However, nearly all PC patients develop resistance to androgen-deprivation therapy (ADT). It has been well established that the progression of PC to castration-resistant growth and development of ADT resistance is associated with aberrant activation of Akt/mTOR signaling. Importantly, PI3K/Akt/mTOR axis acts as a transcriptional integrator of the androgen signaling pathway in PC cells. For many years, the cholesterol homeostasis in PC has been one of the main focuses of research. The consistent interest in the relationship between cholesterol and PC was largely driven by cholesterol involvement in de novo androgen synthesis. Our preliminary studies indicate that major cholesterol fractions (i.e. LDL, HDL, and VLDL) augment activation of Akt/mTOR signaling in PC cells, which coincides with resistance to ENZ. Sensitivity to ENZ was successfully reinstated following treatment with Akt/mTOR inhibitors. Based on these findings, we hypothesize that in addition to serving as a precursor for androgen biosynthesis, lipoprotein- derived cholesterol may promote castration-resistant growth of PC cells via androgen-independent activation of Akt/mTOR pathway. To test our hypothesis and to validate the therapeutic value of targeting cholesterol homeostasis in PC cells in order to increase the antitumor efficacy of ENZ, we propose the following Specific Aims: (1) To establish the role of cholesterol homeostasis in enzalutamide resistance; (2) To improve the antitumor efficacy of enzalutamide by targeting cellular cholesterol homeostasis. We anticipate that the proposed studies will gain insights that suggest new therapeutic options for the treatment of PC.