Targeting Mutant KRAS for Cancer Therapy

 描述(由申请人提供)：这项杰出研究人员奖(OIA)申请的总体目标是识别和验证具有突变KRAS的人类癌症的新靶点和治疗剂。在过去的30年里，已经积累了压倒性的证据，表明突变的KRAS在人类癌症发病机制和患者对治疗的耐药性方面做出了重大贡献，但还没有突变的KRAS抑制剂进入临床试验。NCI已经认识到这是在临床结果方面取得重大进展的主要挑战和障碍。这个OIA应用程序建立在PI的跟踪记录和 在RAS领域的化学生物学和药物发现领域的专业知识，并提出了一个全面的研究计划，专注于靶向KRAS及其信号通路，以开发针对依赖突变KRAS生存和恶性肿瘤的人类肿瘤的新型药物。该应用程序将致力于在许多方面解决这一具有挑战性的问题的研究，在4个程序下集合了几种创新方法，重点是：1)通过识别与突变KRAS结合并降低其对GTP亲和力的小分子，以及那些结合KRAS并抑制其与其效应器结合的小分子，直接靶向突变KRAS；2)通过抑制依赖突变的KRAS的双重FT和GGT-1抑制剂在人类癌症中的前烯基化来间接靶向KRAS，以及通过靶向依赖于老年蛋白的GGT-1抑制剂在人类肿瘤中靶向KRAS转化所需的下游靶点；3)了解突变的KRAS抑制P53的机制，寻找这一途径中的新的可用药靶点并克服对Mt KRAS的依赖。这将包括机制研究以及确定mt KRAS致癌所依赖的信号网络，重点是抑制其在依赖mt KRAS生存的肿瘤中合成致命的蛋白；4)发现仅在携带mt KRAS的人类肿瘤细胞表面表达的蛋白质，最终目标是开发工具来检测具有KRAS突变的人类肿瘤细胞，跟踪治疗进展，并将识别出的蛋白质用作设计新型抗癌药物的靶点。拟议的OIA研究计划将导致重大发现，这些发现将导致专门针对肿瘤中含有突变KRAS的患者的治疗。这将有助于克服对NCI的使命具有高度优先和长期意义的“突变的KRAS挑战”。

 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.