A New Mechanism for Castration Resistant Prostate Cancer

首席研究员/项目主任(最后、第一、中间)：孙子杰 项目摘要 查尔斯·哈金斯和克拉伦斯·霍奇斯发明雄激素已经将近60年了 前列腺癌治疗中的剥夺疗法。已经开发了许多不同的药物，并 此后应用于患者以实现雄激素减少或雄激素受体(AR)抑制，但 剥夺雄激素背后的基本前提几乎没有改变。大多数患者发展为 激素难治性肿瘤，也称为去势抵抗前列腺癌(CRPC)，在两到三年内 在开始治疗后，没有有效的治疗方法。 肝细胞生长因子/分散因子(HGF/SF)是一种多功能的生长因子，在多种细胞因子中发挥重要作用。 在调节细胞生长、细胞运动、形态发生和血管生成方面起关键作用。HGF/SF发挥其功能 通过其受体c-Met，一种跨膜受体酪氨酸激酶(RTK)发挥作用。异常的表情 HGF/SF和c-Met的表达往往与癌症患者的预后不良有关。一种旁分泌机制，用于 HGF/SF对c-Met的刺激在很大程度上与前列腺癌的进展有关。一直以来 显示肝细胞生长因子显著增加恶性上皮细胞的增殖、运动和侵袭能力 通过c-Met蛋白。有趣的是，AR和c-Met的表达呈负相关 已经在前列腺癌细胞中观察到。据报道，去势后c-Met的表达增加 动物8、14和转移性前列腺癌标本。这些数据表明c-Met在 促进疾病进展、抵抗去势和转移。 以前，我们的团队和其他人已经证明AR抑制前列腺中c-Met的表达 癌细胞。具体地说，我们发现AR阻断了Sp1诱导的c-Met转录激活。 这些发现表明，AR既是转录激活因子，又是转录抑制因子，具有双重调节作用 前列腺癌进展的一个新的分子机制。而当 雄激素消融治疗抑制AR诱导的促生长基因表达的激活， 它还可以减弱AR对c-Met表达的抑制作用，增加肿瘤细胞中c-Met的表达。 由于c-Met的过度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果和延迟时间 致CRPC。因此，在这个RO1应用中，我们提出了三个独特但集成的具体目标来进一步测试 我们的中心假设：通过同时雄激素消融治疗抑制AR活性增加c-Met 表达从而诱导雄激素不敏感和前列腺癌更具侵袭性的表型，以及 联合抑制AR和c-Met通路可以阻止或延缓CRPC的发展。主要目标是 使用与生物相关的系统将我们的板凳工作转移到床边，这将导致一部小说 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在前列腺癌形成和发展中的作用，2)作为原则证据，我们将直接 确定c-Met抑制和雄激素消融对前列腺肿瘤生长和生长的联合作用 3)我们将进一步探讨AR抑制c-Met表达的分子机制 在AR和c-Met途径中发现未来的治疗靶点。 项目说明第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