Ligand-Directed KRAS G12V Mutant-Specific Therapeutics

配体导向的 KRAS G12V 突变特异性治疗

• 批准号: 10757070
• 负责人: Chad V Pecot
• 金额: $ 27.56万
• 依托单位: ENFUEGO THERAPEUTICS INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-05 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10757070
• 关键词: Ablation; Acceleration; Address; Affinity; Biodistribution; Biological; Cancer Etiology; Cancer Model; Cancer cell line; Cell Proliferation; Cessation of life; Characteristics; Chemicals; Chemistry; Circulation; Colon; Data; Development; Drug Kinetics; Drug Targeting; Endosomes; Epidermal Growth Factor Receptor; Exhibits; Genes; Genetic Engineering; Growth; Half-Life; Hepatocyte; Hour; Human; Immune; In Vitro; Investigational Drugs; Investigational New Drug Application; KRAS oncogenesis; KRAS2 gene; Kidney; Lead; Libraries; Ligands; Liquid substance; Liver; Lung; Lung Adenocarcinoma; Lung Neoplasms; MAP Kinase Gene; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Modeling; Modification; Molecular; Molecular Abnormality; Mus; Mutation; Non-Malignant; Nucleic Acids; Nucleotides; Oligonucleotides; Oncogenic; Operative Surgical Procedures; Organ; PIK3CG gene; Pancreas; Pathway interactions; Pharmacodynamics; Phase; Phosphorylation; Proteins; Proto-Oncogenes; RNA Interference; Readiness; Safety; Serum; Signal Transduction; Small Business Innovation Research Grant; Small Interfering RNA; Technology; Testing; Therapeutic; Thermodynamics; Tissues; Toxic effect; Transcript; Tumor Burden; United States; Vertebral column; Xenograft Model; cancer cell; cancer therapy; feasibility testing; improved; in vivo; kinase inhibitor; knock-down; lipid nanoparticle; locked nucleic acid; lung cancer cell; mortality; mouse model; mutant; neoplastic cell; novel; novel therapeutic intervention; patient derived xenograft model; pharmacokinetics and pharmacodynamics; phase 2 study; phase 2 testing; phosphorothioate; preservation; programs; safety assessment; safety study; scale up; small molecule; subcutaneous; success; targeted treatment; tumor

Project Summary The proto-oncogene KRAS is one of the most critical genes in cancer, yet, as a drug target, it has proven to be among the most elusive. A remarkable 30% of lung adenocarcinomas, 45% of colon, and 98% of pancreatic cancers are driven by KRAS mutations. These cancers account for the top 3 causes of cancer-related deaths in the United States. Most cancer associated KRAS mutations result in a constitutively active protein, which drives aberrantly high downstream signaling of pro-proliferative and pro-survival effectors including the MAPK and PI3K pathways. Kinase inhibitors have revolutionized treatment of many cancers driven by other molecular aberrations, yet, unfortunately a lack of such success in KRAS-driven cancers has led to KRAS itself to be widely regarded as “undruggable”. EnFuego Therapeutics, Inc. (EFTX) was founded to address the growing number of “undruggable” targets in cancer using RNA interference (RNAi)-based therapeutics. RNAi is particularly attractive for KRAS targeting because it can be optimized to enable selective silencing of mutant transcripts while sparing wild type transcripts, which is important for maintaining normal function in nonmalignant tissue. Mutation-specific therapeutics against KRAS are under development by several companies such as Amgen and Mirati, and rely on small molecules (specific only to G12C mutations). Unlike prior RNAi strategies in cancer, the EFTX approach employs nucleotide modification and ligand conjugation chemistries to promote in vivo stability and affinity-based targeting in cancer cells. In particular, ligand conjugation represents a significant advantage over legacy delivery technologies such as lipid nanoparticles. We have shown that EnFuego siRNAs targeting mutant KRAS transcripts result in: 1) reduced oncogenic MAPK signaling, 2) reduced cancer cell proliferation, and 3) reduced tumor burden in murine cancer models. Based on these preliminary data, this Fast Track program will further develop EFTX siRNA technologies for targeting mutant KRAS in humans. During Phase I, we will focus on optimization of fully chemically modified (FM) siRNA compounds that potently and specifically silence mutant G12V transcripts, exhibit serum stability and immune stealth, and inhibit downstream cancer cell signaling. Two to three FM siRNAs will be selected as lead compound candidates for progression to Phase II studies. Phase II Specific Aims will focus on optimization of pharmacokinetics, tissue targeting, and efficacy in murine models of metastatic lung cancer. These data will inform the selection of a single candidate for scale up and a 4-week GLP safety assessment study. As such, this Fast Track program will accelerate progression of this novel therapeutic strategy toward filing an Investigational New Drug application for metastatic lung cancer therapy.

项目概要 原癌基因 KRAS 是癌症中最关键的基因之一，但作为药物靶点，它已被证明 成为最难以捉摸的人之一。高达 30% 的肺腺癌、45% 的结肠癌和 98% 的胰腺癌 癌症是由 KRAS 突变驱动的。这些癌症占癌症相关的前 3 位原因 美国的死亡人数。大多数癌症相关的 KRAS 突变都会产生一种组成型活性蛋白， 它驱动促增殖和促生存效应器的异常高的下游信号传导，包括 MAPK 和 PI3K 通路。激酶抑制剂彻底改变了许多由其他因素引起的癌症的治疗 分子畸变，然而，不幸的是，在 KRAS 驱动的癌症中缺乏这样的成功，导致 KRAS 其本身被广泛认为是“不可成药的”。 EnFuego Therapeutics, Inc. (EFTX) 的成立是为了解决 使用基于 RNA 干扰 (RNAi) 的疗法发现越来越多的癌症“不可成药”靶点。 RNAi 对于 KRAS 靶向特别有吸引力，因为它可以经过优化以实现突变体的选择性沉默 转录本，同时保留野生型转录本，这对于维持非恶性细胞的正常功能非常重要 组织。多家公司正在开发针对 KRAS 的突变特异性疗法，例如 Amgen 和 Mirati，并依赖小分子（仅针对 G12C 突变）。与之前的 RNAi 策略不同 在癌症中，EFTX 方法采用核苷酸修饰和配体缀合化学来促进 癌细胞中的体内稳定性和基于亲和力的靶向。特别地，配体缀合代表 与脂质纳米粒子等传统递送技术相比具有显着优势。我们已经证明 EnFuego siRNA 靶向突变 KRAS 转录物导致：1) 致癌 MAPK 信号传导减少，2) 减少 癌细胞增殖，3) 减少小鼠癌症模型中的肿瘤负荷。基于这些初步 数据显示，该快速通道计划将进一步开发 EFTX siRNA 技术，用于靶向突变 KRAS 人类。在第一阶段，我们将重点关注完全化学修饰 (FM) siRNA 化合物的优化，这些化合物 有效且特异性地沉默突变 G12V 转录本，表现出血清稳定性和免疫隐形性，并抑制 下游癌细胞信号传导。将选择两到三个 FM siRNA 作为先导化合物候选物 进展至 II 期研究。第二阶段的具体目标将侧重于药代动力学、组织的优化 转移性肺癌小鼠模型的靶向性和疗效。这些数据将告知单个的选择 扩大规模和为期 4 周的 GLP 安全评估研究的候选者。因此，该快速通道计划将 加速这一新治疗策略的进展，以提交研究性新药申请 用于转移性肺癌治疗。