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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：
10209682
负责人：
KEVIN M. SHANNON
金额：
$ 53.18万
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 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10209682
关键词：
Acute Myelocytic Leukemia Address Adult Alleles Antineoplastic Agents Bioavailable Biochemical Biochemistry Biological Models Biology CRISPR interference Cancer Cell Growth Cell Line Cell membrane Cells Chemical Actions Chemicals Co-Immunoprecipitations Collaborations Complex Cysteine Data Development Drug Targeting Enzymes Exhibits Family Foundations Funding GOLGA7 gene Genotype Goals Growth Hematologic Neoplasms Human Individual Knock-in Mouse Knowledge Lead Malignant Childhood Neoplasm Malignant Neoplasms Measures Modeling Molecular Mus Mutant Strains Mice Mutate Mutation Myelogenous NRAS gene Normal tissue morphology Oncogenic Output Pathway interactions Pre-Clinical Model Production Property Protein Isoforms Proteins RAS genes RAS inhibition Ras Inhibitor Reaction Research Personnel Role Serine Hydrolase Signal Transduction Structure Testing Therapeutic Transferase Xenograft procedure acute myeloid leukemia cell base cancer cell conditional mutant drug development drug discovery experimental study in vivo inhibitor/antagonist innovation leukemia mutant novel novel strategies novel therapeutic intervention palmitoylation pre-clinical ras GTPase-Activating Proteins ras Proteins targeted agent targeted treatment therapeutic target trafficking transcriptome

项目摘要

SPECIFIC AIMS Oncogenic RAS mutations, which are among the most common molecular alterations in cancer, encode mutant proteins that dominantly drive aberrant growth. Unfortunately, structural and biochemical properties of the mutant Ras/GTPase activating protein (Ras/GAP) molecular switch pose formidable barriers to mechanism-based drug discovery and no targeted therapies have been approved for Ras-driven cancers to date. The Ras palmitoylation/depalmitoylation cycle regulates the subcellular trafficking of the N-Ras, H-Ras, and K-Ras4a isoforms, but not of K-Ras4b. Thus, developing potent and selective inhibitors of the Ras palmitoylation/depalmitoylation cycle has the potential to treat malignancies dependent on oncogenic N-Ras without interfering with K-Ras4b signaling in normal tissues. This ongoing project involves a cross-disciplinary collaboration between investigators with complementery expertise in biochemistry, chemical biology, hematologic cancer, Ras signaling, and preclinical therapeutics. During the current funding period we: (1) validated N-Ras palmitoylation as a promising therapeutic target for NRAS mutant cancers in a novel strain of NrasG12D,C181S “knock in” mice; (2) identified the ABHD17 family of serine hydrolase (SH) enzymes as N-Ras depalmitoylases; (3) showed that the Palmostatin class of SH inhibitors are too promiscuous for use as selective probes of ABHD17 function; (4) identified, in collaboration with Lundbeck, a structurally distinct class of selective ABHD17 inhibitors that reduce the growth of NRAS mutant acute myeloid leukemia (AML) cells and exhibit genotype-specific activity in isogenic models; and, (5) demonstrated that reduced growth of NRAS mutant AML cells treated with ABHD17 inhibigtors correlates with biochemical inhibition of Ras effector pathways. The experiments proposed in this renewal application will extend these exciting studies through the following specific aims: Aim 1. To investigate the roles of ABHD17s and additional SH enzymes in N-Ras depalmitoylation and to test the potent and bioavailable ABHD17 inhibitor ABD778 in preclinical models of AML; and, Aim 2. To identify palmitoyl acyl transferase (PAT) proteins that modify N-Ras and to validate them as targets for N-Ras mutant cancers. We anticipate that the studies described in this interdisciplinary project will determine fundamental mechanisms of N-Ras palmitoylation, ascertain the efficacy and mechanism of action of chemical inhibitors of ABHD17s alone and in combination with other targeted agents, and generate essential foundational knowledge for developing PAT inhibitors as anti-cancer drugs. The development of selective inhibitors of oncogenic N-Ras signaling would have significant therapeutic impact for a number of different aggressive adult and pediatric cancers.

特定的目标