Development of EFTX-001 to target KRAS mutations in cancer

开发 EFTX-001 以靶向癌症中的 KRAS 突变

• 批准号: 9906510
• 负责人: Chad V Pecot
• 金额: $ 22.5万
• 依托单位: ENFUEGO THERAPEUTICS INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906510
• 关键词: Accounting; Address; Adult; Biological Assay; Bone Marrow; Cancer Etiology; Cancer Model; Cell Line; Cell Survival; Cessation of life; Clinical Trials; Codon Nucleotides; Collaborations; Colon; Colon Carcinoma; Development; Dose; Dose-Limiting; Europe; FDA approved; Formulation; Genes; Goals; Hepatocyte; In Vitro; International; KRAS2 gene; Kidney; Lead; Legal patent; Licensing; Liver; Lung Adenocarcinoma; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Messenger RNA; Missense Mutation; Mitogen-Activated Protein Kinases; Modeling; Molecular Abnormality; Mus; Mutate; Mutation; Neoplasm Metastasis; Oncogenes; Oncology; Pharmaceutical Preparations; Phase; Proto-Oncogenes; RNA Interference; RNA delivery; Research; Signal Transduction; Small Business Innovation Research Grant; System; Technology; Testing; Therapeutic; Therapeutic Index; Thermodynamics; Tissues; Toxic effect; Treatment Efficacy; Universities; Work; base; clinically relevant; efficacy study; experimental study; first-in-human; human disease; in vivo; in vivo Model; in vivo evaluation; inhibitor/antagonist; kidney cell; kinase inhibitor; lead candidate; lipid nanoparticle; mutant; nanoparticle delivery; precision drugs; precision medicine; success; systemic toxicity; tumor; tumor progression

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.

研究摘要： KRAS原癌基因是癌症中最关键的基因之一，但也被证明是 最难以捉摸。密码子12或13中几乎所有（98％）的KRAS错义突变发生，这导致一致性 KRAS激活和促进​​许多癌症标志。尽管激酶抑制剂彻底改变了 处理其他分子畸变驱动的癌症亚群的处理，突变体缺乏这种成功 KRAS驱动的癌症已导致Kras本身被广泛认为是“不可能的”。虽然有G12C 目前正在开发抑制剂，这些疗法仅限于一个KRAS突变，仅考虑 〜12％的KRAS突变，因此在治疗范围上有限。我们已经建立了一个C公司 Enfuego Therapeutics，Inc。通过使用RNA来解决癌症中越来越多的“不良困难”靶标 干扰（RNAI）基于治疗。 RNAi很有吸引力，因为它可以使癌症靶标保持沉默 不能使用常规方法抑制。我们有几条证据表明我们的铅药EFTX- 001，可能会使大多数错义突变沉默并释放WT序列。使用FDA批准 脂质纳米颗粒（LNP）输送系统，我们已经发现了递送的令人印象深刻的治疗潜力 肺癌模型中的EFTX-001无可检测到的毒性。综上所述，关键问题出现，例如：1） 哪些KRAS错义突变最有可能由EFTX-001靶向？ 2）LNP- EFTX-001在健康的成年组织（例如肝脏，肾脏和骨髓）上具有吗？ 3）什么是什么 KRAS依赖性癌症模型中的LNP-EFTX-001？我们假设LNP-EFTX-001可能会沉默 在保留野生型序列的同时，肺和结肠癌中的多个临床上的KRAS突变； 因此，具有高度满足的工厂毒性特征，抑制肿瘤进展。目标的目标 提案是：1）定义潜在的EFTX-001在避开最常见的KRAS突变的目标 WT序列，2）评估EFTX-001对MAP激酶信号传导和细胞活力的影响，3）在体外使用 和体内模型，以确定癌症和成人的WT KRAS与WT KRAS的治疗指数 组织分别。