Development of EFTX-001 to target KRAS mutations in cancer

开发 EFTX-001 以靶向癌症中的 KRAS 突变

基本信息

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
项目类别：
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

项目摘要

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.

研究总结： KRAS 原癌基因是癌症中最关键的基因之一，但它也被证明是几乎所有 (98%) 的 KRAS 错义突变都发生在密码子 12 或 13 中，这会导致组成型突变。尽管激酶抑制剂已经发生了革命性的变化，但 KRAS 的激活和促进了许多癌症标志。治疗由其他分子畸变驱动的某些癌症亚型，在突变体中缺乏这样的成功 KRAS驱动的癌症导致KRAS本身被广泛认为是“不可成药的”，尽管有G12C。目前正在开发的抑制剂，这些疗法仅限于一种 KRAS 突变，仅占约 12% 的 KRAS 突变，因此治疗范围有限，我们建立了 C Corporation， EnFuego Therapeutics, Inc. 利用 RNA 解决癌症中越来越多的“不可成药”靶点基于干扰（RNAi）的疗法很有吸引力，因为它能够沉默癌症靶标。我们有多种证据表明我们的主要药物 EFTX- 无法被抑制。 001，使用 FDA 批准的序列，有效沉默大多数错义突变并保留 WT 序列。脂质纳米颗粒（LNP）输送系统，我们已经发现了令人印象深刻的治疗潜力 EFTX-001 在肺癌模型中没有检测到毒性，因此出现了一些关键问题，例如：1) EFTX-001 最有效地靶向哪些 KRAS 错义突变？ 2) LNP- 有哪些毒性作用？ EFTX-001对健康成人组织（如肝脏、肾脏和骨髓）有什么作用？ LNP-EFTX-001 在 KRAS 依赖性癌症模型中的作用？我们发现 LNP-EFTX-001 会有效沉默肺癌和结肠癌中存在多个临床相关的 KRAS 突变，同时保留野生型序列；因此，以非常令人满意的毒性特征抑制肿瘤进展。建议是：1) 定义 EFTX-001 如何有效地靶向最常见的 KRAS 突变，同时避免 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) 体外使用和体内模型以确定沉默突变体与 WT KRAS 在癌症和成人中的治疗指数组织，分别。