Targeting Mutant KRAS for Cancer Therapy

针对突变 KRAS 进行癌症治疗

• 批准号: 10413104
• 负责人: SAID M SEBTI
• 金额: $ 77.12万
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10413104
• 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; 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（由申请人提供）：这项杰出研究者奖 (OIA) 申请的总体目标是识别和验证突变 KRa 的人类癌症的新靶点和治疗药物，过去 3 年来积累的压倒性证据证明了 KRa 的重大贡献。突变 KRas 会影响人类癌症发病机制和患者肿瘤对治疗的耐药性，但目前还没有突变 KRas 抑制剂进入临床试验，NCI 认为这是在 OIA 应用方面取得重大进展的主要挑战和障碍。建立在 PI 的跟踪记录之上，并且 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，重点关注 KRas 及其信号通路，以开发针对依赖突变型 KRas 生存和恶性的人类肿瘤的新型药物。将从事在多个方面解决这一挑战性问题的研究，通过 4 个项目中汇集的几种创新方法，重点关注：1）通过识别结合突变型 KRas 并降低其与 GTP 亲和力的小分子，直接靶向突变型 KRas。 KRas 并抑制其与其效应子的结合；2) 在依赖于突变型 KRas 的人类癌症中，通过使用 FT 和 GGT-1 双重抑制剂抑制 KRas 的异戊二烯化来间接靶向 KRas，以及在癌症中使用 GGT-1 抑制剂靶向 KRas 转化所需的下游靶标。依赖于牻牛儿基牻牛儿化蛋白的人类肿瘤，3) 了解突变型 KRas 抑制 p53 的机制，识别该途径中新的可药物靶点并克服 mt KRas 依赖性。这将包括机制研究以及识别 mt KRas 所依赖的导致癌症的信号网络，重点是激酶，这些激酶的抑制在依赖 mt KRas 生存的肿瘤中具有综合致死性，4) 发现专门表达的蛋白质。在含有 mt KRas 的人类肿瘤细胞表面上进行研究，最终目标是开发工具来检测具有 KRas 突变的人类肿瘤细胞，跟踪治疗进展并使用已识别的蛋白质作为目标来设计新型抗癌药物。拟议的 OIA 研究计划将产生重大发现，从而产生专门针对具有突变 KRas 的肿瘤患者的治疗方法，这将有助于克服“突变 KRas 挑战”，这对于 NCI 的使命具有高度优先性和长期相关性。 。

项目成果

RBM33 directs the nuclear export of transcripts containing GC-rich elements.

• DOI: 10.1101/gad.349456.122
• 发表时间: 2022-05-01
• 期刊: GENES & DEVELOPMENT
• 影响因子: 10.5
• 作者: Thomas, Anu;Rehfeld, Frederick;Zhang, He;Chang, Tsung-Cheng;Goodarzi, Mohammad;Gillet, Frank;Mendell, Joshua T.
• 通讯作者: Mendell, Joshua T.

Subcellular and in-vivo Nano-Endoscopy.

• DOI: 10.1038/srep34400
• 发表时间: 2016-10-03
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Cheemalapati SV;Winskas J;Wang H;Konnaiyan K;Zhdanov A;Roth A;Adapa SR;Deonarine A;Noble M;Das T;Gatenby R;Westerheide SD;Jiang RH;Pyayt A
• 通讯作者: Pyayt A

The human malaria parasite genome is configured into thousands of coexpressed linear regulatory units.

• DOI: 10.1016/j.jgg.2020.08.005
• 发表时间: 2020-09-20
• 期刊: JOURNAL OF GENETICS AND GENOMICS
• 影响因子: 5.9
• 作者: Wang, Chengqi;Gibbons, Justin;Adapa, Swamy R.;Oberstaller, Jenna;Liao, Xiangyun;Zhang, Min;Adams, John H.;Jiang, Rays H. Y.
• 通讯作者: Jiang, Rays H. Y.