A New Mechanism for Castration Resistant Prostate Cancer

主要研究者/项目负责人（末、首、中）：孙子杰 项目摘要 自从查尔斯·哈金斯和克拉伦斯·霍奇斯发明雄激素以来， 前列腺癌的治疗方法有哪些？已经开发了许多不同的药物， 应用于患者以达到雄激素减少或雄激素受体（AR）抑制，但 雄激素剥夺背后的基本前提几乎保持不变。大多数患者发展为 激素难治性肿瘤，也称为去势抵抗性前列腺癌（CRPC）， 治疗开始后，没有有效的治疗方法。 肝细胞生长因子/分散因子（HGF/SF）是一种多功能生长因子， 在调节细胞生长、细胞运动、形态发生和血管生成中起关键作用。HGF/SF发挥其 通过其受体c-Met（一种跨膜受体酪氨酸激酶（RTK））发挥作用。异常表达 在癌症患者中，HGF/SF和c-Met的水平通常与不良预后相关。一种旁分泌机制 HGF/SF刺激c-Met在很大程度上与前列腺癌的进展有关。已经 显示HGF显著增加恶性上皮细胞的增殖、运动和侵袭 通过c-Met蛋白。有趣的是，AR和c-Met的表达之间呈负相关， 已经在前列腺癌细胞中观察到。据报道，在去势大鼠中，c-Met表达增加， 动物8、14和转移性前列腺肿瘤样品中。这些数据表明c-Met在以下方面的关键作用： 促进疾病进展、去势抵抗和转移。 以前，我们的小组和其他人已经证明，AR抑制前列腺中的c-Met表达， 癌细胞具体来说，我们确定AR中断Sp1诱导的c-Met转录激活。 这些发现表明AR作为转录激活因子和抑制因子的双重调节作用， 前列腺癌细胞，并暗示了前列腺癌进展的新分子机制。而 雄激素消除疗法抑制由AR诱导的生长促进基因表达的激活， 它还减弱AR对c-Met表达的抑制作用，并增加肿瘤细胞中的c-Met。 由于c-Met的过表达与更具侵袭性的肿瘤表型直接相关，因此增加c-Met 标准雄激素消融治疗的抑制剂可显著改善临床结局， 到CRPC。因此，在此RO 1应用程序中，我们提出了三个独特但集成的具体目标，以进一步测试 我们的中心假设：通过同时进行雄激素阻断治疗来抑制AR活性会增加c-Met 表达，从而诱导雄激素不敏感性和更侵袭性的前列腺癌表型，和 AR和c-Met通路的共同抑制可以预防或延迟CRPC的发展。主要目标是 使用生物相关系统将我们的工作转化为床边工作，这将导致一部小说 用于治疗晚期前列腺癌的治疗策略。三个具体目标是：1）我们将直接评估 c-Met在前列腺癌形成和进展中的作用，2）作为原则上的证明，我们将直接 确定c-Met抑制和雄激素消除对前列腺肿瘤生长的联合作用， 进展，3）我们将进一步探索AR抑制c-Met表达的分子机制， 发现AR和c-Met通路中的未来治疗靶点。 项目描述第6页

Principal Investigator/Program Director (Last, first, middle): Sun, Zijie Project Summary It has been almost 60 years since Charles Huggins and Clarence Hodges invented androgen deprivation therapy for the treatment of prostate cancer. Many different medications have been developed and applied to patients to achieve androgen reduction or androgen receptor (AR) suppression since then, but the fundamental premise behind androgen deprivation has remained almost unchanged. Most patients develop hormone refractory tumor, also known as castration resistant prostate cancer (CRPC) within two to three years following initiation of therapy, for which there is no effective treatment. The hepatocyte growth factor/scatter factor (HGF/SF) is a multifunctional growth factor that plays a critical role in the regulation of cell growth, cell motility, morphogenesis, and angiogenesis. HGF/SF exerts its effects through its receptor, c-Met, a transmembrane receptor tyrosine kinase (RTK). The aberrant expression of HGF/SF and c-Met often correlates with poor prognosis in cancer patients. A paracrine mechanism for HGF/SF stimulation of c-Met has been largely implicated in the progression of prostate cancer. It has been shown that HGF significantly increases the proliferation, motility, and invasion of malignant epithelial cells through the c-Met protein. Interestingly, an inverse correlation between the expression of the AR and c-Met has been observed in prostate cancer cells. An increase in c-Met expression was reported in castrated animals 8, 14, and in metastatic prostate tumor samples. These data suggest a critical role for c-Met in promoting disease progression, castration resistance, and metastasis. Previously, our group and others have demonstrated that the AR represses c-Met expression in prostate cancer cells. Specifically, we identified that the AR interrupts Sp1-induced activation of c-Met transcription. These findings suggest a dual regulatory role for the AR as both a transcriptional activator and a repressor in prostate cancer cells, and imply a novel molecular mechanism for prostate cancer progression. While androgen ablation therapy suppresses activation of the growth promoting gene expression induced by the AR, it also attenuates the repressive role of the AR on c-Met expression and increases the c-Met in tumor cells. Since overexpression of c-Met directly correlates with more aggressive tumor phenotypes, adding c-Met inhibitors to standard androgen ablation therapy may significantly improve the clinical outcome and delay time to CRPC. Thus, in this RO1 application we propose three unique but integrated specific aims to further test our central hypothesis: Inhibition of AR activity through concurrent androgen ablation therapy increases c-Met expression thereby inducing androgen-insensitivity and more aggressive phenotypes of prostate cancer, and co-inhibition of AR and c-Met pathways can prevent or delay CRPC development. The major objective is to use biologically relevant systems to translate our bench work to the bedside, which will lead to a novel therapeutic strategy for treating advanced prostate cancer. Three specific aims are 1) we will directly assess the role of c-Met in prostate cancer formation and progression, 2) as proof-in-principle, we will directly determine the combined effects of c-Met inhibition and androgen ablation on prostate tumor growth and progression, and 3) we will further explore the molecular mechanism for AR repression of c-Met expression to discover future therapeutic targets in the AR and c-Met pathways. Project Description Page 6