TRAIL Mediated Apoptosis in Renal Cell Carcinoma

描述(由申请人提供)： 这是为Peter E.Clark医学博士申请NIDDK指导的临床科学家发展奖，是对NOT-DK-03-004：NIDDK泌尿外科医生职业发展计划的回应。晚期肾细胞癌(RCC)是一种致命的化疗耐药疾病，通常采用干扰素α(IFNA)等生物疗法进行治疗。晚期肾细胞癌需要新的治疗形式。APO2配体/肿瘤坏死因子相关凋亡诱导配体(APO2 Ligand/TRAIL)是肿瘤坏死因子超家族成员之一，优先诱导肿瘤细胞发生凋亡，是一种极具潜力的抗肿瘤药物。TRAIL在动物肿瘤模型中耐受性良好，包括肾癌在内的各种癌症的初步临床试验正在进行中。TRAIL介导的细胞凋亡依赖于其含有同源受体DR4和DR5的死亡结构域(DD)以及DD适配分子FADD。TRAIL介导的信号转导可能受两个缺乏功能DD的受体DcR1和DcR2以及其他下游细胞凋亡调节因子(Flip、Bel家族成员等)的调控。这个项目研究了肾细胞癌中TRAIL受体信号的三个互补方面。我们的初步研究表明，IFNA和TRAIL协同增加了肾癌细胞的死亡。在第一个目标中，我们将确定这种情况发生的分子机制。在其他癌症中，TRAIL及其受体的表达可以预测预后，但在肾癌中尚未进行研究。在第二个目标中，我们将分析一大群特征良好的肾癌患者，以确定TRAIL及其同源受体的表达水平，并检验这是否可以预测临床结果。最后，在多种癌症中，DR4和DR5存在功能上有意义的体细胞突变，但这在肾癌中尚未被研究。在目标3中，我们将鉴定肾细胞癌中的突变并确定它们的功能意义。综上所述，这些研究为TRAIL在肾癌中的作用提供了详细的描述，并为TRAIL与IFNA联合治疗肾癌以及使用TRAIL受体水平和/或突变作为临床预后标志物提供了机制基础。

DESCRIPTION (provided by applicant): This is an application for a NIDDK Mentored Clinical Scientist Development Award for Peter E. Clark, M.D. and is in response to NOT-DK-03-004: NIDDK Career Development Programs for Urologic Surgeons. Advanced renal cell carcinoma (RCC) is a deadly, chemotherapy resistant disease usually treated with biologic therapy such as interferon alpha (IFNa). New forms of therapy for advanced RCC are needed. Apo2 ligand/Tumor necrosis factor related apoptosis inducing ligand (TRAIL) is a member of the TNF superfamily and is an attractive potential anti-tumor agent as it induces apoptosis preferentially in malignant cells. TRAIL is well tolerated in animal tumor models and preliminary clinical trials are ongoing in various cancers, including RCC. TRAIL mediated apoptosis is dependent on its death domain (DD) containing cognate receptors, DR4 and DR5, as well as the DD adaptor molecule FADD. TRAIL mediated signaling may be modulated by two receptors that lack a functional DD, DcR1 and DcR2 and by other downstream regulators of apoptosis (FLIP, Bel family members, etc.). This project examines three complementary aspects of TRAIL receptor signaling in RCC. Our preliminary studies indicate that IFNa and TRAIL cooperate to increase RCC cell death. In aim one we will determine the molecular mechanism by which this occurs. In other cancers the expression of TRAIL and its receptors predicts outcome but this has not been studied in RCC. In aim two we will analyze a large well characterized cohort of RCC patients to determine the expression level of TRAIL and its cognate receptors and test if this predicts clinical outcome. Finally, functionally significant somatic mutations exist in DR4 and DR5 in a variety of cancers but this has not been studied in RCC. In aim 3 we will identify mutations in RCC and determine their functional significance. Together, these studies provide a detailed picture of the role of TRAIL in RCC and could provide a mechanistic basis for combining TRAIL with IFNa as therapy for RCC and using TRAIL receptor levels and/or mutations as clinical prognostic markers.