Targeting Mutant KRAS for Cancer Therapy

 描述（由申请人提供）：该杰出研究者奖（OIA）申请的总体目标是鉴定和验证具有突变KRas的人类癌症的新靶点和治疗剂。在过去的30年里，已经积累了大量证据，证明突变型KRas对人类癌症发病机制和患者肿瘤对治疗的耐药性有重大贡献，但还没有突变型KRas抑制剂进入临床试验。NCI已经认识到这是一个重大的挑战和障碍，使临床结果的重大进展。内审办的这一申请建立在PI的跟踪记录基础上， 该研究所拥有Ras领域化学生物学和药物发现领域的专业知识，并提出了一项全面的研究计划，重点是靶向KRas及其信号通路，以开发特异性针对依赖突变KRas生存和恶性肿瘤的人类肿瘤的新型药物。该申请将从事研究，在许多方面解决这一具有挑战性的问题，并在4个项目下组装了几种创新方法，重点是：1）通过鉴定结合突变KRas并降低其对GTP亲和力的小分子，以及结合KRas并抑制其与其效应物结合的小分子，直接靶向突变KRas; 2）在依赖突变KRas的人类癌症中通过用FT和GGT-1双重抑制剂抑制其异戊二烯化来间接靶向KRas，以及用GGT-1靶向KRas转化所需的下游靶标。1抑制剂在人类肿瘤中依赖于香叶基香叶基化蛋白，3）理解突变KRas抑制p53的机制，鉴定该途径中的新的可药用靶标并克服mt KRas依赖性。这将包括机制研究以及识别mt KRas依赖于引起癌症的信号网络，重点是激酶，其抑制在依赖mt KRas生存的肿瘤中是合成致死的，4）发现仅在携带mt KRas的人类肿瘤细胞表面表达的蛋白质，最终目标是开发检测具有KRas突变的人类肿瘤细胞的工具，跟踪治疗进展，并利用已鉴定的蛋白质作为靶点设计新型抗癌药物。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携带突变KRas的患者的疗法。这将有助于克服“突变KRas挑战”，这是高度优先和长期相关的国家癌症研究所的使命。

 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.