Admin-Core-001

管理核心-001

• 批准号: 10025409
• 负责人: CHANNING J. DER
• 金额: $ 6.48万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-22 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10025409
• 关键词: Address; Administrative Coordination; Alleles; Antineoplastic Agents; Belief; Biochemical; Biological; Biometry; Cancer Etiology; Cessation of life; Clinic; Collaborations; Colorectal Cancer; Complement; Development; Failure; Family; Frequencies; Gene Family; Genetic; Genetically Engineered Mouse; Goals; Human; Individual; KRAS2 gene; Laboratories; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Mutate; Mutation; Oncogenes; Oncogenic; Oncoproteins; Pharmaceutical Preparations; Pharmacology; Portraits; Protein Isoforms; Proteomics; Public Health; RAS genes; Renaissance; Research Personnel; Resolution; Role; Signal Transduction; Structure; Technology; base; cancer genome; cancer therapy; cohesion; design; drug development; drug discovery; genome sequencing; innovation; inter-institutional; interest; melanoma; mutant; novel strategies; productivity loss; programs; ras Oncogene; targeted treatment; therapy development; treatment strategy; tumorigenesis

The RAS oncogenes (HRAS, KRAS and NRAS) comprise the most frequently mutated oncogene family in cancer. Despite more than three decades of intensive effort, presently no effective RAS-targeted therapies have reached the clinic. Contributing to this failure have been missteps and mistakes made in drug development, resulting from the field underestimating the complexities of RAS. While recent cancer genome sequencing studies have provided a more comprehensive genetic portrait of specific cancers, they have also verified that RAS mutations are the major drivers of cancers that comprise three of the four major causes of cancer deaths in the US (lung, colorectal and pancreatic cancer). A “RAS Renaissance” has now begun, with renewed intense interest and effort to identify and develop new pharmacologic strategies to target aberrant RAS function for cancer treatment. Our rationale for this Program Project is based on our belief that key issues regarding RAS function remain to be resolved and that their resolution will be vital to facilitate more knowledgeable and effective approaches for anti-RAS drug discovery. Our overall premise is that RAS mutations are not created equal. Our overarching hypotheses are that there are significant differences among RAS isoforms and RAS mutations, and that these have distinct oncogenic consequences in different cancers. Four Projects comprise our P01, each led by a long-standing RAS researcher who brings complementary and distinct experimental expertise to a Program designed for strong inter-project collaborations that leverage our strengths and minimize our weaknesses. Collectively, we will produce a cohesive and comprehensive study that could not be achieved by individual laboratories working on their own. Our structural, biochemical and biological efforts will identify RAS isoform- and mutation-specific perturbations to RAS function. In the long term, these distinct perturbations may represent targetable vulnerabilities that will reveal new approaches to develop mutation-specific anti-RAS therapies for cancer treatment. Project 1 focuses on cellular studies of KRAS mutations in pancreatic cancer, closely coordinated with the structural and biochemical studies of KRAS in Project 2. Project 2 studies of NRAS are complemented by Project 3 studies of mutant NRAS and wild type RAS alleles in melanoma. Project 4 will use genetically engineered mouse models of lung cancer to address the basis for the preferential mutation of KRAS in cancer. Core A will provide financial oversight, administrative coordination of information exchange, and biostatistics support across this inter-institutional Program Project. Core B will provide innovative proteomics technologies for unbiased profiling of RAS mutation-selective effector signaling. Our Program findings will help to reshape anti-RAS drug discovery with the goal of developing therapies targeting specific subsets of RAS mutations. Relevance to Public Health: RAS mutations are very common in three of the top four causes of US cancer deaths. Development of effective anti-RAS treatment strategies will significantly reduce the loss of productivity and human lives to cancer.

Ras Oncogens（Hras，Kras和Nras）Compis compis是大多数柔和的致癌基因家族 癌症。 到达诊所。 发育是由现场造成的，而癌症的复杂性则是近期的癌症基因组。 测序研究为特定癌症提供了更全面的遗传肖像，它们也有 证实RAS突变是癌症的主要驱动因素，包括四个主要原因 美国的癌症死亡（肺，结直肠癌和胰腺癌）。 重新识别和制定新的药理学策略以瞄准异常的兴趣和努力 RAS的癌症治疗功能。 有关RAS功能的问题仍有待解决，其解决方案对于copilitemore至关重要 我们的整体前提是知识渊博的有效方法。 突变并非平等。 RAS同工型和RAS突变，并且在不同的癌症中具有明显的致癌助剂。 四个项目包括我们的P01，每个项目由一位长期存在的RAS研究人员领导，他带来了编译和 针对旨在强大的项目间合作设计的计划，具有独特的实验专业知识 优势并最小化我们的弱点。 这是由自己的结构，生化和 长期对RAS功能的同工型和突变特异性扰动 术语，这些独特的扰动可能代表可定位的漏洞，揭示了新的方法 开发针对癌症治疗的突变特异性抗RAS疗法。 胰腺癌中的KRAS突变与KRAS的结构和生化研究密切协调 在项目2中。项目2的项目研究补充了突变NRA和野生类型的项目3 黑色素瘤中的无拉斯 癌症中克拉斯的优先突变的基础。 信息交流的协调以及在这方面的生物统计学支持，这是这样的 核心B将主要用于RAS突变选择性的无偏分析的创新蛋白质组学技术 效应子信号传导。 开发针对RAS突变特定子集的疗法。 在美国癌症死亡的前四个原因中，很常见。 治疗策略将大大降低癌症生产力和人类生命的丧失。