Development of novel RAS inhibitory agents for cancer therapy

 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了解取得了很大进展，但到目前为止，有效的RAS治疗抑制剂的开发一直令人失望。鉴于RAS基因突变在人类癌症中的频率，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。我们的建议代表了一种应对这一挑战的新方法。我们将开发高亲和力试剂，专门针对人类肿瘤中最常见的四个突变的KRAS等位基因。目的1将利用单体平台作为一种方法来分离针对以下KRAS突变蛋白的高度特异的亲和试剂：G12D、G12V、G12C和G13D。这些试剂的特异性和效力将在体外确定。目的2将确定这些KRAS突变特异性单体体在消除KRAS驱动的肿瘤与其他癌基因驱动的肿瘤的致瘤表型方面的特异性和选择性。这些研究代表了一种开发高度特异的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，这个项目与NCI的使命高度相关，即以RAS依赖的癌症为目标，这是弗雷德里克国家癌症研究实验室最近的RAS倡议的证据。

 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.