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，其中包括一些癌症，例如 超过 90% 的胰腺癌肿瘤中存在 RAS 突变，尽管 RAS 的突变激活会改变 RAS。 对于 GTP 结合状态，许多致癌 RAS 蛋白的特征是高内在核苷酸 因此，这些 RAS 突变体（称为“快速交换”突变体）会短暂释放 GTP 和 继我们之前获得的 MERIT 奖之后，又通过了无核苷酸 (apo) 状态。 开发特异性和选择性结合 apoRAS 的高亲和力工具生物制剂（Monobodies），我们有 做出了范式转变的发现，即这些脱辅基特异性单体可作为快速-的有效抑制剂 交换，致癌 RAS 突变体的初步研究表明，这些 Monobodies 抑制两者。 使用这些强大的 RAS 突变体，可以研究快速交换而非慢速交换的信号传导和致癌活性。 工具生物制剂，我们将： 1. 确定这些 apoRAS Monobodies 对各种 RAS 突变体的选择性 和 RAS 家族成员；2. 评估靶向 apoRAS 作为抑制策略的可行性和选择性 RAS介导的信号传导和体外致癌转化；3.确定靶向apoRAS的功效； 体内作为治疗 RAS 突变胰腺癌的治疗策略；以及 4. 开发我们的 apoRAS- 鉴于人类 RAS 突变的普遍性，将特定的 Monobodies 纳入临床前抗 RAS 治疗。 癌症以及 RAS 在驱动癌症发生和进展中的重要性，特别是胰腺癌 尽管几十年来，开发抑制患者 RAS 的新方法至关重要。 RAS 领域的研究导致 FDA 批准的药物抑制剂的缺乏，最近 开创性工作为最终开发抗 RAS 疗法带来了新的希望。 启动特异性靶向基于硫醇的RAS(G12C)突变蛋白的药物临床试验 尽管初步结果令人鼓舞，但这些抑制剂仅适用于 G12C 突变的反应性。 G12C 突变型肿瘤约占所有 RAS 突变型癌症的 15%，占胰腺癌的不到 2% 然而，我们的研究结果适用于超过 50% 的 RAS 突变癌症，包括更多。 因此，我们在本次 MERIT 更新中提出的研究将提供超过 45% 的 RAS 突变胰腺癌。 对抑制 RAS 介导的肿瘤发生的新方法的重要见解，因此可能具有广泛的应用前景 更重要的是，这项工作对退伍军人以及广大民众都有好处。 然而，RAS 突变癌症的发病率较高，例如肺癌。 据报道，退伍军人群体中的癌症和胰腺癌的发病率高达 5-7 倍 尤其与我们退伍军人的健康相关。