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Probing RAS-mediated signaling mechanisms with monobody inhibitors

使用单体抑制剂探索 RAS 介导的信号传导机制

基本信息

批准号：
10220892
负责人：
SHOHEI KOIDE
金额：
$ 55.1万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10220892
关键词：
Address Advisory Committees Affinity Amino Acids Antibodies BRAF gene Binding Binding Proteins Biochemical Biochemistry Biological Biology Biophysics Cause of Death Cells Charge Chimera organism Clinical Communities Coupled Development Dimerization Environment Event Extracellular Domain FDA approved Family GTP Binding Genetically Engineered Mouse Goals Grant Growth Growth Factor Guanosine Triphosphate Guanosine Triphosphate Phosphohydrolases Human In Vitro Individual International KRAS2 gene Laboratories Malignant Neoplasms Malignant neoplasm of pancreas Mediating Mission Modality Modeling Molecular Mutate Mutation NRAS gene National Cancer Institute Oncogenes Oncogenic Oncoproteins Oxidation-Reduction Pathway interactions Patients Pharmaceutical Preparations Phosphotransferases Play Prevalence Process Protein Engineering Protein Isoforms Proteins Public Health RAS genes RAS inhibition Ras Inhibitor Reagent Research Risk Role Series Signal Transduction Site Specificity Structure Surface System Talents Technology Tertiary Protein Structure Testing Therapeutic United States Work anticancer research base cancer therapy cell growth chemical genetics empowered experimental study genetic approach in vivo inhibitor/antagonist innovation insight mutant novel novel strategies pre-clinical prevent protein function raf Kinases ras Proteins receptor recruit steroid hormone receptor success targeted treatment therapeutically effective tool tumor tumorigenesis tumorigenic

项目摘要

Project Summary: Cancer is a leading cause of death in the United States and worldwide. As such the President of the United States has recently established the White House Cancer Moonshot Task Force, the mission of which is to eliminate cancer as we know it. Part of this mission is to encourage development of novel cancer treatments. This innovative multi-PI proposal represents a novel approach to this challenge. Oncogenic activation of the RAS family of GTPases occurs in ~30% of cancers making it the most frequently mutated oncogene in human cancers. Despite a great deal of progress in our understanding of the biochemistry of RAS and it's role in tumorigenesis, development of effective therapeutic inhibitors of RAS to date has been disappointing. Thus, there remains a critical need to develop targeted inhibitors of this oncoprotein for treatment of patients with Ras-positive tumors. Using an unbiased, protein engineering approach, we have developed a highly specific and potent inhibitor of H-RAS and K-RAS based on the monobody platform. Monobodies are single-domain proteins of ~95 amino acids that achieve levels of affinity and selectivity similar to antibodies yet are insensitive to the redox potential of their environment. High affinity monobodies have been isolated to a diverse array of targets including the extracellular domain of receptors, kinases, steroid hormone receptors, and modular protein domains. Using this protein-based monobody inhibitor as a powerful experimental tool, we will probe the function of RAS in the tumorigenic process in ways that have not previously been possible. We propose three major aims to accomplish our goal of interrogating RAS function in oncogenesis. In Aim 1, we will use genetically encoded versions of our monobody inhibitor, termed NS1, to address unanswered questions regarding RAS function. In particular, NS1 blocks RAS through binding an allosteric interface important for dimerization of RAS and stimulation of signaling and transformation. Using NS1, we will address the importance of RAS dimerization in activation of multiple RAS effector pathways as well as probe the isoform specific difference in effector engagement. Aim 2 will employ a unique chemical-genetic approach to regulate NS1 expression in vivo to address whether targeting this novel allosteric interface interferes with RAS- dependent tumorigenesis. Building on our recent success with NS1, Aim 3 will develop isoform specific inhibitory monobodies to each RAS isoform and determine their mechanism of action. These studies represent a unique and powerful approach toward studying RAS and defining potential novel approaches to blocking RAS action. Thus, our work has the potential to make a major impact on cancer therapy. In addition, this project is highly relevant to the mission of National Cancer Institute's RAS Initiative at the Frederick National Laboratory for Cancer Research which is charged with targeting RAS-dependent cancers as well as President Obama's Cancer Moonshot initiative. We anticipate that our studies will answer important questions regarding RAS function in cancer while also providing powerful new experimental tools for the wider scientific community to utilize in interrogating RAS function.

项目总结: