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 原癌基因KRAS是癌症中最关键的基因之一，然而，作为药物靶点，它已被证明是 是最难以捉摸的值得注意的是，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疾病的前3位 死亡在美国。大多数癌症相关的KRAS突变导致组成型活性蛋白， 其驱动促增殖和促存活效应物的异常高的下游信号传导， MAPK和PI3K通路。激酶抑制剂已经彻底改变了许多癌症的治疗，这些癌症是由其他 然而，不幸的是，在KRAS驱动的癌症中缺乏这种成功，导致了KRAS 它本身被广泛认为是“不可抵抗的”。EnFuego Therapeutics，Inc.（EFTX）成立的目的是解决 使用RNA干扰（RNAi）为基础的治疗方法在癌症中发现越来越多的“不可治疗”的靶点。RNAi 对于KRAS靶向是特别有吸引力的，因为它可以被优化以使得能够选择性沉默突变体 转录本，而保留野生型转录本，这对于维持非恶性肿瘤细胞的正常功能是重要的。 组织.针对KRAS的突变特异性疗法正在由几家公司开发， Amgen和Mirati，并依赖于小分子（仅对G12C突变特异）。与先前的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，以促进 体内稳定性和癌细胞中基于亲和力的靶向。特别地，配体缀合表示配体缀合。 与传统递送技术如脂质纳米颗粒相比具有显著优势。我们已经证明 靶向突变型KRAS转录物的EnFuego siRNA导致：1）致癌MAPK信号传导减少，2）致癌MAPK信号传导减少， 癌细胞增殖，和3）降低鼠癌症模型中的肿瘤负荷。基于这些初步 数据，这个快速通道计划将进一步开发EFTX siRNA技术，用于靶向突变的KRAS， 人类在第一阶段，我们将专注于优化完全化学修饰的（FM）siRNA化合物， 有效地和特异性地沉默突变G12V转录物，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， 进入II期研究。II期特定目标将重点关注药代动力学、组织 在转移性肺癌的鼠模型中的靶向和功效。这些数据将告知选择一个单一的 用于规模扩大和4周GLP安全性评估研究的候选药物。因此，这一快速通道计划将 加速这种新型治疗策略的进展，以提交研究性新药申请 转移性肺癌的治疗