Ligand-Directed KRAS G12V Mutant-Specific Therapeutics

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，它已经被证明 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突变引起的。这些癌症占癌症相关原因的前三位。 美国的死亡人数。大多数与癌症相关的KRAS突变都会导致一种结构性活性蛋白， 它驱动促增殖和支持生存的效应器的下游信号异常高，包括 MAPK和PI3K通路。激酶抑制剂使许多癌症的治疗发生了革命性的变化，这些癌症是由 然而，不幸的是，在KRAS驱动的癌症中缺乏这种成功导致了KRAS 被广泛认为是“不能下药的”。Enfuego治疗公司(EFTX)的成立是为了解决 使用基于RNA干扰(RNAi)的疗法治疗癌症中越来越多的“无法用药”的靶点。RNAi 对于KRAS靶向特别有吸引力，因为它可以被优化以实现突变的选择性沉默 转录本，同时保留野生型转录本，这对维持非恶性疾病的正常功能很重要 组织。针对KRAS的突变特异性疗法正在由几家公司开发，如 安进和米拉蒂，依赖小分子(仅针对G12C突变)。与以前的RNAi策略不同 在癌症中，EFTX方法使用核苷酸修饰和配体结合化学来促进 癌细胞的体内稳定性和基于亲和力的靶向。具体地说，配体共轭代表一种 与传统的传递技术，如脂质纳米粒相比，具有显著的优势。我们已经证明了 针对突变KRAS转录本的enfuego siRNAs导致：1)癌基因MAPK信号转导减少，2)减少 癌细胞增殖，以及3)降低了小鼠癌症模型中的肿瘤负担。基于这些初步的 数据，这一快速跟踪计划将进一步开发EFTX siRNA技术，用于靶向突变的KRAS 人类。在第一阶段，我们将重点研究完全化学修饰(FM)siRNA化合物的优化 有效和特异地沉默突变的G12V转录本，表现出血清稳定性和免疫隐蔽性，并抑制 下游癌细胞信号。将选出两到三个FM siRNA作为候选的先导化合物 进展到第二阶段研究。第二阶段的具体目标将集中在优化药代动力学、组织 在转移性肺癌小鼠模型中的靶向性和有效性。这些数据将通知您选择一个 扩大规模和为期4周的GLP安全评估研究的候选人。因此，该快速通道计划将 加快这一新的治疗策略向提交调查性新药申请的进展 用于转移性肺癌的治疗。

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.