Defining RAS isoform- and mutation-specific roles in oncogenesis

定义 RAS 异构体和突变在肿瘤发生中的特异性作用

• 批准号: 9302699
• 负责人: CHANNING J. DER
• 金额: $ 154.24万
• 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/9302699
• 关键词: Address; Administrative Coordination; Alleles; Antineoplastic Agents; Belief; Biochemical; Biological; Biometry; Cancer Etiology; Cessation of life; Clinic; Collaborations; Colorectal Cancer; Complement; Defect; Development; Failure; Family; Frequencies; Gene Family; Genetic; Genetically Engineered Mouse; Goals; Growth; HRAS gene; Human; Individual; KRAS2 gene; Knowledge; Laboratories; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Motivation; Mutate; Mutation; Oncogenes; Oncogenic; Oncoproteins; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacological Treatment; Pharmacology; Phosphoproteins; Portraits; Property; Protein Isoforms; Protein Kinase; Proteins; Proteomics; Public Health; RAS genes; Recording of previous events; Renaissance; Research; Research Personnel; Research Support; Resolution; Role; Signal Transduction; Technology; base; cancer cell; cancer genome; cancer survival; cancer therapy; clinical application; cohesion; design; drug development; drug discovery; experience; genome sequencing; innovation; innovative technologies; inter-institutional; interest; melanoma; mouse model; mutant; novel strategies; premature; productivity loss; programs; protein function; ras Oncogene; research study; success; targeted treatment; therapy development; treatment strategy; tumorigenesis

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：RAS 癌基因（HRAS、KRAS 和 NRAS）包含癌症中最常见突变的癌基因家族。尽管经过三十多年的努力，目前还没有有效的 RAS 靶向疗法进入临床。导致这一失败的原因是药物开发过程中的失误和错误，这是由于该领域低估了 RAS 的复杂性造成的。虽然最近的癌症基因组测序研究提供了特定癌症的更全面的基因图谱，但他们也证实了 RAS 突变是癌症的主要驱动因素，这些癌症构成了美国癌症死亡的四个主要原因中的三个（肺癌、结直肠癌和胰腺癌）。 “RAS 复兴”现已开始，人们重新产生了浓厚的兴趣并努力确定和开发新的药理学策略，以异常的 RAS 功能为目标进行癌症治疗。我们开展该计划的理由是基于我们的信念，即有关 RAS 功能的关键问题仍有待解决，并且这些问题的解决对于促进更明智、更有效的抗 RAS 药物发现方法至关重要。我们的总体前提是 RAS 突变并非生而平等。我们的首要假设是 RAS 异构体和 RAS 突变之间存在显着差异，并且它们在不同的癌症中具有不同的致癌后果。我们的 P01 包括四个项目，每个项目均由一位长期担任 RAS 研究员领导，他为项目带来了互补且独特的实验专业知识，旨在实现强有力的项目间合作，从而利用我们的优势并最大限度地减少我们的劣势。我们将共同开展一项有凝聚力和全面的研究，这是各个实验室单独工作无法完成的。我们的结构、生化和生物学工作将识别 RAS 亚型和突变对 RAS 功能的特定扰动。从长远来看，这些独特的扰动可能代表了可针对的脆弱性，这将揭示开发用于癌症治疗的突变特异性抗 RAS 疗法的新方法。项目 1 重点关注胰腺癌 KRAS 突变的细胞研究，与项目 2 中 KRAS 的结构和生化研究密切配合。项目 2 对 NRAS 的研究得到项目 3 对黑色素瘤中突变 NRAS 和野生型 RAS 等位基因的研究的补充。项目 4 将使用肺癌基因工程小鼠模型来解决癌症中 KRAS 优先突变的基础。核心 A 将在整个机构间计划项目中提供财务监督、信息交换的行政协调和生物统计支持。 Core B 将提供创新的蛋白质组学技术，用于对 RAS 突变选择性效应信号进行公正的分析。我们的计划研究结果将有助于重塑抗 RAS 药物的发现，目标是开发针对特定 RAS 突变子集的疗法。与公共卫生的相关性：RAS 突变在美国癌症死亡的四大原因中的三个中非常常见。开发有效的抗 RAS 治疗策略将显着减少癌症造成的生产力损失和人类生命。