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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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要诊断患有晚期 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，但预后患有这些癌症的患者仍然很穷，5年生存率<10%。近期，取得了进展在专门针对 KRASG12C 突变的治疗方法的临床进展中取得了进展，这些突变是存在于大约百分之五的结直肠肿瘤中。然而，用 KRASG12C 进行的单一疗法试验有针对性的药物虽然令人鼓舞，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 会响应下游信号重新激活 MAPK 激酶信号传导干预，这一事件因 PI3K/mTOR 通路在介导中的作用而进一步复杂化反抗。该提案的中心假设是，一种双重小分子抑制剂能够有效且选择性靶向 EGFR 和 PI3 激酶代表了一种与 KRASG12C 抑制剂临床候选药物 AMG-510。为了验证这个假设，我们设计了小分子对 EGFR 和 PI3K 家族成员表现出有效和选择性的双重抑制作用。我们建议开展一项我们的双 EGFR/PI3K 先导分子 MTX-531 与 AMG-510 组合在异种移植模型中的小鼠试验由诊断为 KRASG12C 突变结直肠癌的患者建立。分子谱分析将旨在阐明与固有敏感性以及适应性信号传导相关的标记导致进展的变化。响应者模型将在头对头的验证性测试中重新评估与西妥昔单抗和 AMG-510 组合的头部比较。该提案的总体目标是展示临床前概念验证，以追求这一发展路径以优化治疗 MTX-531 作为治疗 KRASG12C 突变结直肠癌的精准医学方法的潜力癌症。