Targeting Castration Resistant Prostate Cancer via Potent Inhibition of Signaling Lipids

摘要 转移性去势抵抗前列腺癌通常是致命的，是导致癌症的第二大原因。 美国男性癌症相关死亡人数。尽管多西紫杉醇的治疗取得了进展，但阿比特龙 和苯扎鲁胺，前列腺癌进展为致命的去势抵抗前列腺癌(CRPC)仍然是一种 主要的临床问题。快速增殖的癌细胞上调新生脂肪生成和胆固醇 合成途径，以便为蛋白质的膜形成和脂质修饰提供脂类，并 支持能源生产。甾醇调节元件结合蛋白(SREBPs)是主要的调节因子 激活编码合成胆固醇和不饱和脂肪酸所需酶的基因的转录因子 脂肪酸。SREBPs在前列腺癌和其他实体肿瘤中经常过度表达，并且 与肿瘤侵袭性和不良结局相关。有趣的是，新出现的研究表明 在非裔美国人(AA)前列腺癌患者中-他们的前列腺癌发病率已经高出1.6倍 前列腺癌死亡率是高加索男性的2.6倍-雄激素受体和 PI3K/Akt/mTOR信号通路比高加索前列腺癌患者更活跃 导致脂类代谢的增加更大。雄激素受体与PI3K/Akt信号通路的激活 转录因子MNX1，导致SREBP1的诱导，控制许多成脂基因的表达 包括FASN在内的基因，并改变前列腺癌细胞的代谢状态。SREBPS的失活 代表了一种新陈代谢驱动的肿瘤靶向的新机制。的首要目标是 这项临床前研究旨在为SREBP抑制剂的使用建立关键的概念验证有效性和安全性数据 抗前列腺癌细胞，使用广泛的体外和体内模型。我们建议的研究主要集中在 1)确定SREBPs在前列腺癌中的功能，并鉴定具有生物学意义的 SREBP激活；2)体外评价SREBP小分子抑制剂的作用及机制；3) 使用细胞评估SREBP抑制剂单独和与现有药物联合使用的抗癌活性 LINE异种移植和创新的前列腺癌患者来源的异种移植模型。

Summary Metastatic castration resistant prostate cancer is uniformly fatal, representing the second-leading cause of cancer-related death among men in the United States. Despite therapeutic advances with docetaxel, abiraterone and enzalutamide, prostate cancer progression to lethal castration-resistant prostate cancer (CRPC) remains a major clinical problem. Rapidly proliferating cancer cells upregulate de novo lipogenesis and cholesterol synthesis pathways in order to provide lipids for membrane formation and lipid modification of proteins and to support energy production. The sterol regulatory element binding proteins (SREBPs) are master regulatory transcription factors that activate genes encoding enzymes required for synthesis of cholesterol and unsaturated fatty acids. The SREBPs are frequently overexpressed in prostate cancer and other solid tumors and are associated with tumor aggressiveness and unfavorable outcomes. Interestingly, emerging studies suggest that in African American (AA) prostate cancer patients - who already have 1.6 times higher prostate cancer incidence and 2.6 times higher mortality from prostate cancer than Caucasian males - the androgen receptor and PI3K/Akt/mTOR signaling pathways are more active than in Caucasian prostate cancer patients, frequently resulting in even greater increase in lipid metabolism. Androgen receptor and the PI3K/Akt signaling can activate the transcription factor MNX1, leading to induction of SREBP1, which controls expression of numerous lipogenic genes including FASN, and alters the metabolic state of the prostate cancer cell. Inactivation of SREBPs represents a novel mechanism by which metabolically-driven tumors can be targeted. The overarching goal of this preclinical study is to establish key proof-of-concept efficacy and safety data for the use of SREBP inhibitors against prostate cancer cells, using extensive in vitro and in vivo models. Our proposed studies are focused on 1) defining the function of SREBPs in prostate cancer and identifying biologically significant lipid products of SREBP activation, 2) evaluating effects and mechanisms of a small molecule inhibitor of SREBP in vitro, and 3) assessing the anticancer activity of SREBP inhibitors alone and in combination with existing drugs, using cell line xenograft and innovative patient-derived xenograft models of prostate cancer.