Development of EFTX-001 to target KRAS mutations in cancer

研究摘要： KRAS原癌基因是癌症中最关键的基因之一，但它也被证明是 非常难以捉摸。几乎所有(98%)的KRAS错义突变都发生在密码子12或13上，这导致了结构性突变 KRAS的激活和促进了许多癌症的标志。尽管激酶抑制剂已经彻底改变了 治疗由其他分子异常驱动的某些癌症亚群，在突变中缺乏这种成功 KRAS引发的癌症导致KRAS本身被广泛认为是“无法用药治疗的”。虽然有G12C 目前正在开发的抑制剂，这些疗法仅限于一个KRAS突变，仅占 ~12%的KRAS突变，因此治疗范围有限。我们成立了一家C公司， Enfuego治疗公司通过使用RNA来解决癌症中越来越多的“无法用药”的靶点 基于干扰(RNAi)的治疗学。RNAi之所以有吸引力，是因为它能够沉默癌症靶点 不能用传统的方法来阻止。我们有几条证据表明我们的先导药物EFTX- 001，有效地沉默了大多数错义突变，并节省了WT序列。使用FDA批准的 脂质纳米粒(LNP)递送系统，我们已经发现了令人印象深刻的治疗潜力 未检测到毒性的肺癌模型中的EFTX-001。综上所述，出现了一些关键问题，例如：1) 哪些KRAS错义突变是EFTX-001最有效的靶点？2)LNP- EFTX-001对健康成人组织(如肝、肾和骨髓)有何作用？3)治疗指数是多少？ KRAS依赖肿瘤模型中的LNP-EFTX-001？我们假设LNP-EFTX-001将有效地沉默 肺癌和结肠癌中多个临床相关的KRAS突变，同时保留野生型序列； 因此，抑制肿瘤进展具有非常令人满意的毒性特征。这样做的目的是 建议是：1)定义EFTX-001针对最常见的KRAS突变的效力，同时避免 WT序列，2)评估EFTX-001对MAP激酶信号转导和细胞活力的影响，3)体外使用 和体内模型确定沉默突变体与WT KRAS对癌症和成人的治疗指数 组织，分别。

Research Summary: The KRAS proto-oncogene is one of the most critical genes in cancer, yet it has also proven to be among the most elusive. Nearly all (98%) of KRAS missense mutations occur in codons 12 or 13, which leads to constitutive KRAS activation and promotion of numerous cancer hallmarks. Although kinase inhibitors have revolutionized treatment of some subsets of cancers driven by other molecular aberrations, the lack of such success in mutant KRAS-driven cancers has led KRAS itself being widely regarded as “undruggable”. Although there are G12C inhibitors currently being developed, these therapies are limited to only one KRAS mutation, accounting for only ~12% of KRAS mutations, and therefore limited in therapeutic scope. We have established a C Corporation, EnFuego Therapeutics, Inc. to address the growing number of “undruggable” targets in cancer by using RNA interference (RNAi)-based therapeutics. RNAi is attractive because it enables silencing of cancer targets that cannot be inhibited using conventional approaches. We have several lines of evidence that our lead drug, EFTX- 001, potently silences the majority of missense mutations and spares the WT sequence. Using an FDA-approved lipid nanoparticle (LNP) delivery system, we have already found impressive therapeutic potential for delivering EFTX-001 in lung cancer models with no detectable toxicity. Taken together, key questions arise, such as: 1) Which KRAS missense mutations are most potently targeted by EFTX-001? 2) What toxic effects does LNP- EFTX-001 have on healthy adult tissue (e.g. liver, kidney and bone marrow)? 3) What is the therapeutic index of LNP-EFTX-001 in KRAS-dependent cancer models? We hypothesize that LNP-EFTX-001 will potently silence multiple clinically-relevant KRAS mutations in lung and colon cancers while sparing the wild-type sequence; consequently, inhibiting tumor progression with a highly satisfactory toxicity profile. The objectives of this proposal are: 1) to define how potently EFTX-001 targets the most common KRAS mutations while sparing the WT sequence, 2) to evaluate the effects of EFTX-001 on MAP kinase signaling and cell viability, 3) use in vitro and in vivo models to determine the therapeutic index of silencing mutant versus WT KRAS in cancer and adult tissues, respectively.