TRAIL Mediated Apoptosis in Renal Cell Carcinoma

肾细胞癌中 TRAIL 介导的细胞凋亡

• 批准号: 7275168
• 负责人: PETER E CLARK
• 金额: $ 12.78万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-29 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7275168
• 关键词: apoptosis; biological signal transduction; clinical research; cysteine endopeptidases; cytokine receptors; flow cytometry; gene mutation; human tissue; immunocytochemistry; interferon alpha; laser capture microdissection; molecular pathology; neoplasm /cancer genetics; nephrectomy; northern blottings; prognosis; receptor expression; renal cell carcinoma; site directed mutagenesis; tumor necrosis factor alpha; western blottings; yeast two hybrid system

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.

描述（由申请人提供）： 这是一个应用程序的NIDDK指导临床科学家发展奖彼得E。克拉克医学博士并回应NOT-DK-03-004：NIDDK泌尿外科医生职业发展计划。 晚期肾细胞癌（RCC）是一种致命的化疗耐药疾病，通常用生物疗法如干扰素α（IFNa）治疗。晚期RCC需要新的治疗形式。Apo 2配体/肿瘤坏死因子相关凋亡诱导配体（tumor necrosis factor related apoptosis inducing ligand，TRAIL）是肿瘤坏死因子超家族成员之一，由于其优先诱导恶性肿瘤细胞凋亡，是一种有吸引力的潜在抗肿瘤药物。TRAIL在动物肿瘤模型中耐受性良好，并且在包括RCC在内的各种癌症中正在进行初步临床试验。TRAIL介导的细胞凋亡依赖于其含有死亡结构域（DD）的同源受体DR 4和DR 5以及DD衔接分子FADD。TRAIL介导的信号传导可由两种缺乏功能性DD的受体DcR 1和DcR 2以及由细胞凋亡的其它下游调节因子（FLIP、Bel家族成员等）调节。本项目研究肾癌中TRAIL受体信号传导的三个互补方面。我们的初步研究表明，IFNa和TRAIL合作增加RCC细胞死亡。在目标一中，我们将确定这种情况发生的分子机制。在其他癌症中，TRAIL及其受体的表达可预测结果，但尚未在RCC中进行研究。在第二个目标中，我们将分析一个大型的RCC患者的良好表征的队列，以确定TRAIL及其同源受体的表达水平，并测试这是否预测临床结果。最后，在多种癌症中，DR 4和DR 5中存在功能显著的体细胞突变，但这在RCC中尚未研究。在目标3中，我们将鉴定RCC中的突变并确定其功能意义。总之，这些研究提供了TRAIL在RCC中的作用的详细描述，并且可以为将TRAIL与IFNa组合作为RCC的治疗以及使用TRAIL受体水平和/或突变作为临床预后标志物提供机制基础。