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Selectively Targeting Oncogenic NRAS in Cancer

选择性靶向癌症中的致癌 NRAS

基本信息

批准号：
9040123
负责人：
KEVIN M. SHANNON
金额：
$ 55.05万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9040123
关键词：
Address Alleles Amino Acids Biochemical Biochemistry Biology Cancer Burden Cancer cell line Cells Characteristics Chemicals Collaborations Cysteine Data Development Dominant-Negative Mutation Enzymatic Biochemistry Enzymes Frequencies Generations Genes Genetic Goals Growth HRAS gene Health Hematologic Neoplasms Hematopoietic Human Knock-in Knock-in Mouse Malignant - descriptor Malignant Neoplasms Methods Molecular Molecular Biology Techniques Mouse Strains Mus Mutant Strains Mice Mutate Mutation NRAS gene Oncogenes Oncogenic Output Pathogenesis Pathway interactions Play Post-Translational Protein Processing Protein Isoforms Proteins Proto-Oncogenes Reagent Reporting Research Personnel Serine Serine Hydrolase Signal Transduction Staging Synthesis Chemistry TAP2 gene Tertiary Protein Structure Testing Therapeutic activity-based protein profiling base cancer cell cancer type cell growth conditional mutant design drug discovery gain of function improved in vivo inhibitor/antagonist leukemia mutant novel novel strategies novel therapeutic intervention palmitoylation pre-clinical progenitor protein function ras GTPase-Activating Proteins ras Proteins research study small molecule libraries therapeutic target trafficking

项目摘要

DESCRIPTION (provided by applicant): RAS proto-oncogenes are mutated in ~30% of human cancers, but no mechanism-based treatments exist for reversing the biochemical output of oncogenic Ras proteins, which are exceedingly difficult targets for rational drug discovery. Our long-term goal is to implement mechanistic strategies to selectively inhibit the growth of cancers with somatic RAS mutations. In this project, we will investigate the Ras palmitoylation/depalmitoylation cycle, which regulates the subcellular trafficking of the N-Ras, H-Ras, and K-Ras4a isoforms, as a therapeutic target for selectively inhibiting the growth of malignancies with oncogenic NRAS mutations. Acyl protein thioesterase 1 and 2 (APT1 and APT2) catalyze N-Ras depalmitoylation and we found that "first generation" chemical inhibitors designed to inhibit these enzymes (Palmostatin B and Palmostatin M) selectively reduced the growth of primary hematopoietic progenitors and leukemia cells expressing oncogenic N-RasG12D. However, our recent studies also infer the existence of additional biochemical targets of these compounds that are essential for the growth of NRAS mutant cancer cells. This project involves a cross-disciplinary collaboration that brings together investigators with extensive expertise in synthetic chemistry (Dr. Howell), enzymology and chemical biology (Dr. Cravatt), and hematologic cancer, Ras signaling, and preclinical therapeutics (Dr. Shannon). We have collaborated to generate extensive preliminary data and novel reagents, which we will use to pursue the goals of: (1) identifying additional biochemical targets of the palmostatins; (2) developing new chemical inhibitors with improved potency and selectivity for palmostatin targets; (3) using these inhibitors combined with genetic methods to discern the relevant enzyme(s) that regulate N-Ras depalmitoylation in cancer cells; and, (4) utilizing human cancer cell lines and a new strain of mice to interrogate the palmitoylation/depalmitoylation cycle as a therapeutic target in early stage and advanced NRAS-mutant cancers. We will address these questions through two highly integrated specific aims. In Aim 1, we will identify additional biochemical targets of palmostatin M, design and characterize new chemical inhibitors, and evaluate the efficacy of these compounds in cancer cells with NRAS mutations. In Aim 2, we will utilize a novel strain of NrasG12D,C181S "knock in" mice to ask if the palmitoylation/depalmitoylation cycle is required for the growth of oncogenic Nras-driven cancers in vivo. These studies will rigorously assess the importance of the palmitoylation/depalmitoylation cycle and inform the development of new therapeutic strategies for cancers with oncogenic RAS mutations.