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

开发新的组合策略来克服结直肠癌对 KRASG12C 抑制的耐药性

• 批准号: 10512415
• 负责人: Judith S Leopold
• 金额: $ 21.88万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10512415
• 关键词: 1-Phosphatidylinositol 3-Kinase; Antibodies; Biological Availability; Biopsy; Cancer Model; Cetuximab; Clinical; Clinical Trials; Colorectal; Colorectal Cancer; Colorectal Neoplasms; Development; Diagnosis; EGFR inhibition; Epidermal Growth Factor Receptor; Evaluation; Event; Exhibits; FRAP1 gene; Family member; Grant; Head; Intervention; KRAS2 gene; Lead; Longevity; Malignant Neoplasms; Measures; Mediating; Mitogen-Activated Protein Kinase Kinases; Modeling; Molecular Profiling; Molecular Target; Mus; Mutate; Mutation; Non-Small-Cell Lung Carcinoma; Oral; PIK3CA gene; Pathway interactions; Patients; Pharmacodynamics; Phase; Phosphorylation; Prognostic Marker; Protein Microchips; Public Health; Resistance; Role; Signal Transduction; Signaling Protein; Survival Rate; Testing; Therapeutic; Time; Tumor-Derived; Xenograft Model; base; clinical candidate; colon cancer patients; comparative efficacy; compare effectiveness; design; effective therapy; efficacy evaluation; efficacy testing; head-to-head comparison; improved; in vivo evaluation; inhibitor; mutant; novel; patient derived xenograft model; patient prognosis; phosphoproteomics; pre-clinical; precision medicine; response; small molecule; small molecule inhibitor; targeted agent; therapy outcome; treatment strategy; tumor

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.

项目摘要/摘要 诊断为晚期KRAS突变结肠癌的患者的总生存率约为 一年。尽管出现了增加分子靶向剂的数量，但对 患有这些癌症的患者仍然很差，5年生存率<10％。最近，进度一直在 专门针对KRASG12C突变的治疗剂的临床进步进行 大约有5％的结直肠肿瘤。但是，用KRASG12C进行的单一疗法试验 有针对性的代理在鼓励的同时遇到了令人失望的缺乏耐用反应，决定了需求 用于组合方法。已知EGFR反应对下游的MAPK激酶信号传导 干预，这一事件使PI3K/MTOR途径在中介中的作用更加复杂 反抗。该提议的中心假设是，双重小分子抑制剂有效，并且 有选择地靶向EGFR和PI3激酶代表了一种可行的治疗策略与 KRASG12C抑制剂临床候选AMG-510。为了检验这一假设，我们设计了小分子 对EGFR和PI3K家庭成员表现出强大而有选择性的双重抑制。我们建议执行 在异种移植模型中，我们的双EGFR/PI3K铅分子MTX-531的小鼠试验与AMG-510结合 由诊断为KRASG12C突变结肠癌的患者建立。分子分析将是 进行以阐明与固有灵敏度以及自适应信号相关的标记 导致进展的变化。响应器模型将在从头到头的确认测试中重新评估 与西妥昔单抗和AMG-510的组合进行比较。该提议的总体目的是 展示临床前的概念证明，以追求这一开发途径以优化治疗 MTX-531作为治疗KRASG12C突变体结直肠癌的精确医学方法的潜力 癌症。