Therapeutic targeting of tumor metabolism in advanced prostate cancer

晚期前列腺癌严重影响美国退伍军人群体。的一个关键特征是， 晚期疾病是一个异常升高的胆固醇生物合成的肿瘤，这可能有助于 前列腺癌的致命进展。然而，这种畸变的机制并不清楚， 这严重阻碍了利用独特的代谢脆弱性， 晚期疾病的治疗干预。回顾性研究的流行病学证据， 包括退伍军人人群，通常将降胆固醇药物他汀类药物的使用与 提高生存率和/或降低晚期疾病的风险。然而，到目前为止， 用他汀类药物进行晚期肿瘤胆固醇合成尚未对患者产生显著的益处。 因此，鉴定和阐明介导胆固醇生物合成异常的关键因素， 晚期前列腺癌的治疗是当务之急。这项建议是基于我们最近发现的一种新的 前列腺癌的治疗靶点，即核受体蛋白ROR γ，以及我们的证据， 进一步的研究表明，受体蛋白和胆固醇中间体可能发挥直接作用， 促进前列腺癌肿瘤细胞中异常的胆固醇合成。我们的初步结果 也表明ROR的小分子抑制剂可以使肿瘤对他汀类药物的杀伤敏感。我们 因此，希望建立ROR蛋白在控制异常胆固醇中的新功能 前列腺癌肿瘤中的合成，定义其功能机制并确定是否靶向 受体蛋白与有效的前列腺癌选择性小分子抑制剂，与 他汀类药物是治疗晚期前列腺癌的一种新的高效治疗策略。

Advanced prostate cancers disproportionally affect veteran populations in the US. One key feature of the advanced diseases is an aberrantly elevated cholesterol biosynthesis for the tumor, which likely contributes to the lethal progression of prostate cancer. However, the mechanisms underlying the aberration are poorly understood, which severely hinders exploitation of the unique metabolic vulnerability for effectively therapeutic intervention of advanced diseases. Epidemiological evidence from retrospective studies, including ones in the veterans populations, generally associate cholesterol-lowering drug statin use with improved survival and/or lower risk of advanced disease. However, thus far, clinical trials targeting advanced tumor cholesterol synthesis with statins have not yet yielded significant benefits to patients. Therefore, identification and elucidation of key factors that mediate the aberrant cholesterol biosynthesis in the advanced prostate cancers is urgently needed. This proposal is based on our recent discovery of a new therapeutic target, namely a nuclear receptor protein RORgamma, for prostate cancer and evidence of our further studies that suggest a possible direct role of the receptor protein and the cholesterol intermediates in promoting the aberrant cholesterol synthesis in the prostate cancer tumor cells. Our preliminary results also suggest that small-molecule inhibitors of the ROR can sensitize tumors to killing by statins. We therefor wish to establish the novel function of the ROR protein in control of the aberrant cholesterol synthesis in prostate cancer tumors, define its functional mechanisms and determine whether targeting the receptor protein with a potent, prostate cancer-selective, small-molecule inhibitor, in combination with statins, is a novel and highly efficacious therapeutic strategy for advanced prostate cancer.