Ligand-Directed KRAS G12V Mutant-Specific Therapeutics

配体导向的 KRAS G12V 突变特异性治疗

基本信息

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
项目类别：
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

项目摘要

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，它已被证明其中肺腺癌占 30%，结肠癌占 45%，胰腺癌占 98%。癌症是由 KRAS 突变驱动的，这些癌症是导致癌症相关的三大原因。在美国，大多数癌症相关的 KRAS 突变都会导致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 通路抑制剂彻底改变了许多其他癌症的治疗方法。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 EnFuego Therapeutics, Inc. (EFTX) 的成立就是为了解决这一问题。使用基于 RNA 干扰 (RNAi) 的疗法来治疗癌症中“不可成药”的靶标数量不断增加。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多家公司正在开发针对 KRAS 的突变特异性疗法，例如 Amgen 和 Mirati 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特别是，配体缀合代表了癌细胞中的体内稳定性和基于亲和力的靶向。我们已经证明，与纳米脂质颗粒等传统输送技术相比具有显着优势。 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。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 在第一阶段，我们将重点关注完全化学修饰（FM）的 siRNA 化合物的优化。有效且特异性地沉默突变 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被选为先导化合物候选物。 II 期进展到 II 期研究的具体目标将侧重于药代动力学、组织的优化。这些数据将为单一药物的选择提供信息。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。