Development of Novel Combination Strategies to Overcome Resistance to KRASG12C Inhibition in Colorectal Cancers

项目概要/摘要 诊断为晚期KRAS突变结直肠癌的患者的总生存期约为 一年尽管出现了越来越多的分子靶向药物， 患有这些癌症的患者仍然很差，5年生存率<10%。最近， 在针对KRASG 12 C突变的特异性治疗的临床进展中， 在大约百分之五的结直肠肿瘤中存在。然而，使用KRASG 12 C进行的单药治疗试验 有针对性的代理人，虽然令人鼓舞，但令人失望的是缺乏持久的反应，这表明需要 对于组合方法。已知EGFR响应于下游信号转导而重新激活MAPK激酶信号传导。 干预，这是一个事件，进一步复杂化的作用PI 3 K/mTOR途径介导的 阻力这一提议的中心假设是，一种双重小分子抑制剂， 选择性靶向EGFR和PI 3激酶代表了一种可行的治疗策略， KRASG 12 C抑制剂临床候选药物AMG-510。为了验证这一假设，我们设计了一些小分子， 表现出对EGFR和PI 3 K家族成员的有效和选择性双重抑制。我们建议进行一项 我们的EGFR/PI 3 K双重先导分子MTX-531联合AMG-510在异种移植模型中的小鼠试验 从诊断为KRASG 12 C突变结直肠癌的患者建立。分子分析将是 进行阐明与固有敏感性以及适应性信号相关的标记物， 这些变化导致进步。应答者模型将在头对头验证性试验中重新评价， 与西妥昔单抗和AMG-510联合治疗的头部比较。本建议的总体目标是 证明了追求这一开发路径的临床前概念验证，以优化治疗 MTX-531作为治疗KRASG 12 C突变结直肠癌的精确药物方法的潜力 癌

PROJECT SUMMARY/ABSTRACT Patients diagnosed with advanced stage KRAS mutant colorectal cancer have an overall survival of roughly one year. Despite the emergence of an increased number of molecular targeted agents, the prognosis for patients with these cancers remains poor with 5-year survival rates of <10%. Recently, progress has been made in the clinical advancement of therapeutics directed specifically against KRASG12C mutations, which are present in roughly five percent of colorectal tumors. However, monotherapy trials conducted with KRASG12C targeted agents, while encouraging, have met with disappointing lack of durable responses, dictating the need for combination approaches. EGFR is known to reactivate MAPK kinase signaling in response to downstream intervention, an event that is further complicated by the role of the PI3K/mTOR pathway in mediating resistance. The central hypothesis of this proposal is that a dual small molecule inhibitor that potently and selectively targets both EGFR and PI3 kinase represents a viable treatment strategy in combination with the KRASG12C inhibitor clinical candidate AMG-510. To test this hypothesis, we have designed small molecules that exhibit potent and selective dual inhibition of EGFR and PI3K family members. We propose to carry out a mouse trial of our dual EGFR/PI3K lead molecule MTX-531 in combination with AMG-510 in xenograft models established from patients diagnosed with KRASG12C mutant colorectal cancer. Molecular profiling will be carried out to elucidate markers that correlate with inherent sensitivity as well as the adaptive signaling changes that lead to progression. Responder models will be re-evaluated in confirmatory testing in head-to- head comparison with the combination of cetuximab and AMG-510. The overall objective of this proposal is to demonstrate preclinical proof of concept for pursuit of this development path to optimize the therapeutic potential of MTX-531 as a precision medicine approach for the treatment of KRASG12C mutant colorectal cancer.