Development of novel RAS inhibitory agents for cancer therapy

开发用于癌症治疗的新型 RAS 抑制剂

基本信息

批准号：
9379114
负责人：
John P O'Bryan
金额：
$ 6.63万
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 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9379114
关键词：
Affinity Alleles Amino Acids Antibodies Biochemistry Biology Cells Clinical Cysteine Data Development Directed Molecular Evolution Environment Frequencies Future Human In Vitro Individual Laboratories Lead Ligands Malignant Neoplasms Malignant neoplasm of pancreas Methods Mission Modality Molecular Conformation Mutate Mutation NIH 3T3 Cells Oncogenes Oncogenic Oncoproteins Oxidation-Reduction Patients Peptide Hydrolases Peptides Phenotype Phosphoric Monoester Hydrolases Point Mutation 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 Treatment Efficacy Tumor Cell Line Tumorigenicity 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 public health relevance 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.

描述（由申请人提供）：尽管我们对 Ras 的生物化学及其在肿瘤发生中的作用的理解取得了很大进展，但鉴于人类癌症中 Ras 突变的频率，迄今为止有效的 Ras 治疗抑制剂的开发仍然令人失望。迫切需要开发这种癌蛋白的靶向抑制剂来治疗 Ras 阳性肿瘤患者，我们的建议代表了应对这一挑战的新方法，我们将开发专门针对四种最常见突变体的高亲和力试剂。人类肿瘤中的 KRas 等位基因将利用单体平台作为分离针对以下 KRas 突变蛋白的高度特异性亲和试剂的方法：G12D、G12V、G12C 和 G13D。这些试剂的特异性和效力将在中确定。然后，目标 2 将确定这些 KRas 突变特异性单体在消除 KRas 驱动的致瘤表型方面的特异性和选择性。这些研究代表了开发高度特异性 Ras 抑制试剂的新方法，因此有可能对癌症治疗产生重大影响。此外，该项目与 NCI 的靶向 Ras 使命高度相关。弗雷德里克国家癌症研究实验室最近发起的 Ras Initiative 提供了证据。