Novel Functions for Ras family GTPases

Ras 家族 GTPases 的新功能

• 批准号: 10396030
• 负责人: John P O'Bryan
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-10-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10396030
• 关键词: Address; Affinity; Antibodies; Automobile Driving; Award; Binding; Binding Proteins; Biochemical; Biological Models; Biological Products; Biology; Cancer Patient; Cells; Chemicals; Clinical Trials; Cytoplasm; Data; Development; Dimerization; Disease; Dissociation; Environment; Equilibrium; Exhibits; FDA approved; Family; Family member; Future; GTP Binding; General Population; Growth; Guanosine Triphosphate; Guanosine Triphosphate Phosphohydrolases; Health; Human; In Vitro; Incidence; KPC model; KRAS oncogenesis; KRAS2 gene; KRASG12D; Knowledge; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Mass Spectrum Analysis; Mediating; Medical; Methods; Modeling; Mutate; Mutation; NRAS gene; Nucleotides; Oncogenic; Organoids; Pancreatic Ductal Adenocarcinoma; Patients; Pharmaceutical Preparations; Pharmacology; Play; Prevalence; Protac; Proteins; Proto-Oncogene Proteins c-akt; Ras Inhibitor; Reagent; Reporting; Research; Role; Signal Transduction; Specificity; Sulfhydryl Compounds; Technology; Therapeutic; Transgenic Organisms; Translations; Tumor-Derived; Veterans; Work; Xenograft procedure; base; cellular targeting; in vivo; inducible gene expression; inhibitor; innovation; insight; military veteran; mimetics; multidisciplinary; mutant; nano; novel; novel strategies; pancreatic neoplasm; patient derived xenograft model; pre-clinical; prevent; ras Proteins; small molecule; targeted treatment; therapeutic development; therapeutic target; three dimensional cell culture; tool; tumor; tumorigenesis

Mutational activation of RAS occurs in approximately 30% of human tumors with some cancers such as pancreatic cancer having RAS mutations in >90% of tumors. Although mutational activation of RAS shifts RAS to the GTP-bound state, a number of oncogenic RAS proteins are characterized by high intrinsic nucleotide dissociation rates. Thus, these RAS mutants, termed “fast-exchange” mutants, transiently release GTP and transit through the nucleotide-free (apo) state. Following on our previous MERIT award that resulted in development of high affinity tool biologics (Monobodies) that specifically and selectively bind apoRAS, we have made a paradigm shifting discovery that these apo-specific Monobodies function as potent inhibitors of fast- exchange, oncogenic RAS mutants. Preliminary studies suggest that these Monobodies inhibit both the signaling and oncogenic activity of fast exchange but not slow exchange RAS mutants. Using these powerful tool biologics, we will: 1. determine the selectivity of these apoRAS Monobodies toward various RAS mutants and RAS family members; 2. assess the viability and selectivity of targeting apoRAS as a strategy to inhibit RAS-mediated signaling and oncogenic transformation in vitro; 3. determine the efficacy of targeting apoRAS in vivo as a therapeutic strategy for treating RAS-mutant pancreatic cancers; and 4. develop our apoRAS- specific Monobodies into a preclinical anti-RAS therapeutic. Given the prevalence of RAS mutations in human cancers and the importance of RAS in driving cancer development and progression, particularly pancreatic cancers, it is critical to develop new approaches to therapeutically inhibit RAS in patients. Although decades of research in the RAS field has resulted in a dearth of FDA-approved pharmacological inhibitors, recent pioneering work has renewed hope in finally developing an anti-RAS therapeutic. Several companies have launched clinical trials of drugs that specifically target the RAS(G12C) mutant protein based on the thiol reactivity of the G12C mutation. Although initial results are promising, these inhibitors will only be useful in G12C-mutant tumors which constitute roughly15% of all RAS-mutant cancers and less than 2% of pancreatic tumors. Our findings, however, would be applicable to more than >50% of RAS mutant cancers including more than 45% of RAS-mutant pancreatic cancers. Thus, our proposed studies in this MERIT renewal will provide critical insights into a novel approach to inhibit RAS-mediated tumorigenesis and are thus likely to have broad translation significance. More importantly, this work will be beneficial to Veterans as well as the general population, both of which suffer from cancer. However, the incidence for RAS mutant cancers, such as lung and pancreatic cancer, has been reported to be up to 5-7x higher in Veteran populations making these studies particularly relevant to the health of our Veterans.

Ras的突变激活发生在大约30％的人类肿瘤中，某些癌症（例如 胰腺癌在> 90％的肿瘤中具有RAS突变。尽管RAS的突变激活使RAS移动 在GTP结合的状态下，许多致癌性RAS蛋白的特征是高固有核苷酸 解离率。这些Ras突变体称为“快速交换”突变体，瞬时释放GTP和 通过无核苷酸（APO）状态过境。遵循我们以前的优点奖 开发高亲和力工具生物制剂（单一化合物），这些生物制剂具体，有选择地结合了aporas，我们有 提出了一个范式转移发现，这些apo特异性单体形成起着快速抑制剂的作用 交换，致癌Ras突变体。初步研究表明，这些单一体抑制了 快速交换的信号传导和致癌活性，而不是慢慢交换RAS突变体。使用这些功能强大 工具生物制剂，我们将：1。确定这些aporas单子对各种RAS突变体的选择性 和RAS家庭成员； 2。评估靶向aporas的生存能力和选择性作为抑制的策略 Ras介导的信号传导和体外致癌转化； 3。确定靶向aporas的效率 体内作为治疗Ras突变胰腺癌的治疗策略；和4。发展我们的aporas- 特异性单体形成临床前抗RAS治疗。考虑到人类RAS突变的流行率 癌症以及RAS在推动癌症发展和进展方面的重要性，尤其是胰腺 癌症，至关重要的是开发新的治疗方法抑制患者的RAS。虽然数十年 RAS领域的研究导致FDA批准的药物抑制剂死亡，最近 开创性的工作使人们最终开发了一种抗RAS治疗。几家公司有 基于硫醇的药物启动了专门针对RAS（G12C）突变蛋白的临床试验 G12C突变的反应性。尽管承诺最初的结果，但这些抑制剂只会在 G12C突变肿瘤大约占所有Ras突变癌的15％，胰腺占不到2％ 肿瘤。但是，我们的发现将适用于超过50％的RAS突变体癌症，包括更多 超过45％的Ras突变胰腺癌。这是我们在此功绩更新中提出的研究将提供 对一种抑制RAS介导的肿瘤发生的新方法的批判性见解，因此很可能具有广泛的 翻译意义。更重要的是，这项工作将对退伍军人以及一般都是有益的 人口，两者都患有癌症。但是，RAS突变癌的事件，例如肺 据报道，胰腺癌的资深人群高达5-7倍 与退伍军人的健康特别相关。