Novel Functions for Ras family GTPases

RAS的突变激活发生在大约30%的人类肿瘤中，其中一些癌症如 在>90%的肿瘤中具有RAS突变的胰腺癌。尽管RAS突变激活使RAS 对于GTP结合状态，许多致癌RAS蛋白的特征是具有高的内在核苷酸水平， 解离速率因此，这些RAS突变体，称为“快速交换”突变体，瞬时释放GTP， 通过无核苷酸（APO）状态的转变。继我们之前的MERIT奖，导致 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 做出了一个范式转变的发现，这些apo特异性单体作为快速- 交换，致癌RAS突变体。初步研究表明，这些Monobodies抑制两个 信号传导和致癌活性的快速交换，但不是慢交换RAS突变体。利用这些强大的 工具生物学，我们将：1。确定这些apoRAS单体对各种RAS突变体的选择性 家庭成员; 2。评估靶向apoRAS作为抑制 RAS介导的信号传导和体外致癌转化; 3.确定靶向apoRAS的疗效 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- 将特异性Monobodies转化为临床前抗RAS治疗剂。考虑到RAS突变在人类中的普遍性， 癌症和RAS在驱动癌症发展和进展中的重要性，特别是胰腺癌。 因此，开发治疗性抑制患者RAS的新方法至关重要。虽然几十年来 RAS领域的研究导致FDA批准的药理学抑制剂的缺乏， 开创性的工作重新燃起了最终开发抗RAS治疗剂的希望。几家公司已经 启动了针对RAS（G12 C）突变蛋白的药物的临床试验， G12 C突变。虽然初步结果是有希望的，但这些抑制剂将仅用于 G12 C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%。 肿瘤的然而，我们的研究结果适用于超过50%的RAS突变型癌症，包括更多的 45%以上的RAS突变胰腺癌因此，我们在这次MERIT更新中提出的研究将提供 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 翻译意义更重要的是，这项工作将有利于退伍军人以及一般 两人都患有癌症。然而，RAS突变型癌症的发病率，如肺癌， 据报道，在这些研究中，退伍军人人群中的胰腺癌发病率高达5- 7倍 这与我们退伍军人的健康特别相关。

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.