Novel Functions for Ras family GTPases

RAS的突变激活发生在大约30%的人类肿瘤中，某些癌症如 胰腺癌在90%的肿瘤中有RAS突变。尽管RAS的突变激活改变了RAS 对于GTP结合状态，一些致癌的RAS蛋白具有高本征核苷酸的特征 离解率。因此，这些被称为“快速交换”突变体的RAS突变体瞬间释放GTP和 通过无核苷酸(Apo)状态。继我们之前的功勋奖之后，导致 开发高亲和力的工具生物制品(单体体)，特异性和选择性地结合apoRAs，我们有 做出了一项改变范式的发现，即这些脱氧核糖核酸单体能有效抑制FAST- 交换，致癌的RAS突变体。初步研究表明，这些单体体既抑制了 快速交换而不是慢交换RAS突变体的信号和致癌活性。使用这些强大的 工具生物制品，我们将：1.确定这些apoRAS单体对各种ras突变体的选择性。 和RAS家族成员；2.评估靶向apoRAS作为一种抑制策略的可行性和选择性 Ras介导的信号转导与体外致癌转化；3.靶向apoRAs的效果测定 体内作为治疗ras突变胰腺癌的策略；以及4.开发我们的apoRAS- 将特异性单抗转化为临床前抗RAS治疗。鉴于RAS突变在人类中的普遍存在 癌症和RAS在推动癌症发生和发展中的重要性，特别是胰腺癌 对于癌症来说，开发新的治疗方法来抑制患者的RAS是至关重要的。尽管几十年来 最近，RAS领域的研究导致缺乏FDA批准的药理抑制剂 开创性的工作重新燃起了人们的希望，最终开发出一种抗RAS疗法。有几家公司已经 启动了针对基于硫醇的RAS(G12C)突变蛋白的药物的临床试验 G12C突变的反应性。尽管初步结果是有希望的，但这些抑制剂只会在 G12C突变肿瘤，约占所有RAS突变癌症的15%，占胰腺癌的不到2% 肿瘤。然而，我们的发现将适用于超过50%的RAS突变癌症，包括更多 超过45%的RAS突变胰腺癌。因此，我们在这次功绩更新方面的拟议研究将提供 对抑制RAS介导的肿瘤发生的新方法的批判性见解因此可能具有广泛的 翻译的意义。更重要的是，这项工作对退伍军人和将军都有好处 人口，这两个人都患有癌症。然而，RAS突变癌症的发病率，如肺癌 和胰腺癌，据报道，在进行这些研究的退伍军人中，发病率高出5-7倍 尤其关系到我们退伍军人的健康。

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.