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

基本信息

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
项目类别：
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

项目摘要

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（由申请人证明）：RAS ONCOGEN（HRAS，KRAS和NRA）组成了癌症中大多数的癌症家族这种失败在药物开发中产生的失败，低估了RAS的复杂性。癌症中的癌症（结直肠癌）现在开始了，以识别和制定新的药理学策略，以实现异常的RAS功能来解决癌症。我们的整体前提是抗RAS药物的方法。专门为我们的劣势而设计的强大的合作，我们将产生一个凝聚力和融合性的研究，而双重实验室无法自行进行生物化学。 RAS功能。这些独特的扰动可能代表可靶向的漏洞4。信号有助于改造抗RAS药物，以发展为h：RAS突变。