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.

项目摘要 原始癌基因KRAS是癌症中最关键的基因之一，但是作为药物靶标的，它已被证明 是最难以捉摸的。肺腺癌的30％，45％的结肠和98％的胰腺 癌症是由KRAS突变驱动的。这些癌症是癌症相关的前三名原因 在美国死亡。大多数癌症相关的KRAS突变导致组成性活性蛋白， 这驱动了促生物促成和促生物效应的异常高的下游信号传导，包括 MAPK和PI3K途径。激酶抑制剂已彻底改变了对许多其他癌症的治疗 分子畸变，但不幸的是，在KRAS驱动的癌症中缺乏这样的成功，导致了Kras 本身被广泛认为是“不可能的”。 Enfuego Therapeutics，Inc。（EFTX）是为了解决的 使用RNA干扰（RNAI）的治疗，癌症中越来越多的“不良”靶标。 RNAi 对于KRAS靶向而言特别有吸引力，因为它可以优化以实现突变体的选择性沉默 传承野生型转录本时的转录本，这对于在非态度中保持正常功能很重要 组织。针对KRAS的突变特异性疗法正在开发中 Amgen和Mirati，并依靠小分子（仅特定于G12C突变）。与先前的RNAi策略不同 在癌症中，EFTX接近员工核苷酸修饰和配体共轭化学以促进 癌细胞中的体内稳定性和基于亲和力的靶向。特别是，配体结构代表 比传统递送技术（例如脂质纳米颗粒）的重要优势。我们已经表明 Enfuego siRNA靶向突变体KRAS转录物的结果：1）降低致癌MAPK信号，2）减少 癌细胞增殖和3）减少了鼠类癌模型中的肿瘤灼伤。基于这些初步 数据，这个快速轨道程序将进一步开发用于靶向突变kras的EFTX siRNA技术 人类。在第一阶段，我们将专注于优化对完全化学修饰的（FM）siRNA化合物的优化 潜在的，特别是沉默的突变体G12V转录本，暴露的血清稳定性和免疫健康，并抑制 下游癌细胞信号传导。两到三个FM SiRNA将被选为铅复合候选者 发展为II期研究。第二阶段的特定目的将集中于优化药代动力学，组织 靶向和有效性在转移性肺癌的鼠模型中。这些数据将告知选择单个的选择 候选人缩放和为期4周的GLP安全评估研究。因此，这个快速轨道计划将 加速这种新型的热策略以提交研究性新药 用于转移性肺癌治疗。