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Development of novel Ras inhibitory agents for cancer therapy"

用于癌症治疗的新型Ras抑制剂的开发"

基本信息

批准号：
9213585
负责人：
John P O'Bryan
金额：
$ 3.14万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
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：
2015-12-01 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9213585
关键词：
Affinity Alleles Amino Acids Antibodies Biochemistry Biology Cells Cysteine Data Development Directed Molecular Evolution Environment Frequencies Future Health Human In Vitro Individual Laboratories Lead Ligand Binding Malignant Neoplasms Malignant neoplasm of pancreas Methods Mission Modality Molecular Conformation Mutate Mutation NIH 3T3 Cells Oncogenes Oncogenic Oxidation-Reduction Patients Peptide Hydrolases Peptides Phenotype Phosphoric Monoester Hydrolases Point Mutation Process Protein Engineering Protein Isoforms Proteins Ras Inhibitor Reagent Research Rewards Risk Role Scheme Signal Transduction Specificity Technology Tertiary Protein Structure Testing Therapeutic Therapeutic Agents Transformed Cell Line Tumor Cell Line Virus-like particle Work anticancer research cancer therapy cross reactivity efficacy testing in vivo individual patient inhibitor/antagonist mutant nanocapsule nanoparticle neoplastic cell novel novel strategies novel therapeutics programs ras Oncogene ras Proteins success tool tumor tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Despite a great deal of progress in our understanding of the biochemistry of Ras and its role in tumorigenesis, development of effective therapeutic inhibitors of Ras to date has been disappointing. Given the frequency of Ras mutations in human cancers, there is a critical need to develop targeted inhibitors of this oncoprotein for treatment of patients with Ras-positive tumors. Our proposal represents a novel approach to this challenge. We will develop high affinity reagents that specifically target the four most frequent mutant KRas alleles in human tumors. Aim 1 will utilize the monobody platform as a method to isolate highly specific affinity reagents that target the following KRas mutant proteins: G12D, G12V, G12C, and G13D. The specificity and potency of these reagents will be determined in vitro. Aim 2 will then determine the specificity and selectivity of these KRas mutation specific monobodies at abrogating the tumorigenic phenotype of KRas-driven tumors vs tumors driven by other oncogenes. These studies represent a novel approach toward developing highly specific Ras inhibitory reagents and thus have the potential to make a major impact on cancer therapy. In addition, this project is highly relevant to the NCI's mission of targeting Ras-dependent cancers as evidence by the recent Ras Initiative at the Frederick National Laboratory for Cancer Research.