Targeting Mutant KRAS for Cancer Therapy

针对突变 KRAS 进行癌症治疗

• 批准号: 10204898
• 负责人: SAID M SEBTI
• 金额: $ 83.93万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10204898
• 关键词: Affinity; Area; Award; Binding; Biology; Cancer Etiology; Cancer Patient; Chemicals; Clinical; Clinical Trials; Dependence; Goals; Guanosine Triphosphate; Human; KRAS2 gene; Malignant Neoplasms; Mission; Mutation; Outcome; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphotransferases; Proteins; Research; Research Personnel; Signal Pathway; Signal Transduction; Surface; TP53 gene; cancer therapy; design; drug discovery; inhibitor/antagonist; innovation; mutant; neoplastic cell; new therapeutic target; novel; novel anticancer drug; novel therapeutics; prenylation; programs; public health relevance; small molecule; targeted treatment; therapy resistant; tool; tumor

 DESCRIPTION (provided by applicant): The overall goal of this Outstanding Investigator Award (OIA) application is to identify and validate novel targets and therapeutic agents for human cancers with mutant KRas. Overwhelming evidence has accumulated over the last 3 decades that demonstrates significant contributions of mutant KRas to human cancer pathogenesis and patient tumor resistance to therapy, yet no mutant KRas inhibitors have reached clinical trials. The NCI has recognized this as a major challenge and obstacle to making significant progress to clinical outcomes. This OIA application builds on the PI's track-record and expertise in the area of chemical biology and drug discovery in the Ras field and proposes a comprehensive research program focused on targeting KRas and its signaling pathways to develop novel agents that are specific for human tumors that depend on mutant KRas for survival and malignancy. The application will engage in research that tackles this challenging problem on many fronts with several innovative approaches assembled under 4 programs focusing on: 1) Directly targeting mutant KRas by identifying small molecules that bind mutant KRas and lower its affinity for GTP, and those that bind KRas and inhibit its binding to its effectors; 2) Indirectly targeting KRas by inhibiting its prenylation with dual FT and GGT-1 inhibitors in human cancers that depend on mutant KRas as well as targeting downstream targets required for KRas transformation with GGT-1 inhibitors in human tumors that depend on geranylgeraylated proteins, 3) Understanding the mechanism by which mutant KRas suppresses p53, identifying novel druggable targets in this pathway and overcoming mt KRas dependency. This will include mechanistic studies as well as identifying signaling networks that mt KRas relies on to cause cancer with an emphasis on kinases whose suppression is synthetically lethal in tumors that depend on mt KRas for survival, 4) Discovering proteins that are expressed exclusively on the surface of human tumor cells that harbor mt KRas with the ultimate goal of developing tools to detect human tumors cells with KRas mutations, to follow treatment progress and to use the identified proteins as targets to design novel anti-cancer drugs. The proposed OIA research programs will result in significant discoveries that will lead to therapies that specifically target patients whose tumors harbor mutant KRas. This will contribute to overcoming the "mutant KRas challenge" that is of high priority and long term relevance to the mission of the NCI.

 描述（由应用程序提供）：该杰出调查员奖（OIA）的总体目标是确定和验证具有突变KRAS的人类癌症的新颖目标和治疗剂。在过去的3年中，有大量的证据积累了，表现出突变KRAS对人类癌症发病机理和患者肿瘤对治疗的重要贡献，但没有突变的KRAS抑制剂进行了临床试验。 NCI认为这是对临床结果取得重大进展的主要挑战和障碍。此OIA应用程序建立在Pi的轨道录像带上，并且 在RAS领域的化学生物学和药物发现领域的专家和提案，一项全面的研究计划，旨在针对KRAS及其信号传导途径，以开发针对依赖突变体Kras生存和恶性肿瘤的人类肿瘤的新型药物。该应用程序将进行研究，以在4个计划下组装的几种创新方法在许多方面解决这个挑战问题：1）通过识别结合突变体KRAS并降低其对GTP的亲和力的小分子，以及将KRAS结合并抑制其结合对其作用的小分子，直接针对突变体KRAS； 2）通过抑制依赖于突变体Kras的人类癌症中的双FT和GGT-1抑制剂来抑制kras的靶向kra，并靶向KRAS在人类肿瘤中使用GGT-1抑制剂转化所需的下游靶标，这些靶标在人类肿瘤中依赖于人类基果蛋白的新型蛋白质，3）在人类肿瘤中抑制了这种抑制kras的机械性，3）途径和克服Kras山的依赖。这将包括机械研究以及识别Kras mt依赖癌症的信号网络，强调抑制在依赖Kras的肿瘤中抑制在合成中致死性的激酶鉴定出蛋白质是设计新型抗癌药物的靶标。拟议的OIA研究计划将导致重大发现，这将导致疗法，这些疗法专门针对肿瘤含有突变体Kras的患者。这将有助于克服与​​NCI任务相关的“突变KRAS挑战”。