Detection of Colorectal Cancer Adaptive Mutability May Justify Combination of Targeted- and Immune-Therapies

结直肠癌适应性突变的检测可能证明靶向治疗和免疫治疗相结合的合理性

基本信息

批准号：
10289627
负责人：
TIMOTHY J YEATMAN
金额：
$ 6.88万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-20 至 2022-04-16
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10289627
关键词：
BRAF gene Biological Assay Biological Markers Biological Sciences Cancer Etiology Cancer cell line Cell Line Cells Cessation of life Colorectal Cancer Combined Modality Therapy Complex DNA DNA Repair Gene DNA sequencing Data Dependence Diagnosis Drug Tolerance Drug resistance Epidermal Growth Factor Receptor Exposure to Gene Expression Profile Gene Frequency Genes Genetic Genome Immune Immune checkpoint inhibitor Immunotherapy Individual KRAS2 gene Lead MEKs Measurable Measures Mediating Microsatellite Instability Mismatch Repair Molecular Molecular Target Mutate Mutation Oncogenes Organoids Pathway interactions Patients Pharmaceutical Preparations Phenotype Polymerase Population Probability Ras Inhibitor Ras Signaling Pathway Ras/Raf Reactive Oxygen Species Reporting Resistance Signal Pathway Signal Transduction Solid Technology Testing Time base biological adaptation to stress biomarker-driven cancer cell checkpoint therapy clinical predictors colon cancer cell line colorectal cancer screening detection limit experimental study gene panel genetic variant genome-wide genotoxicity homologous recombination immune checkpoint immunogenicity improved inhibitor/antagonist mutant mutational status neoantigens novel novel therapeutics patient subsets predicting response predictive marker repair enzyme resistance mechanism response sound targeted agent targeted treatment therapeutic target transcriptome sequencing tumor

项目摘要

PROJECT SUMMARY/ABSTRACT Colorectal cancer (CRC) is a major cause of cancer deaths which is curable if detected early. Unfortunately, many CRC tumors are diagnosed at more advanced stages where cure rates remain low with 20% five-year survival. The EGFR/RAS signaling pathway is a strong driver of CRC when constitutively activated via mutations (KRAS ~40%, BRAF ~10%, NRAS ~5%), but targeted molecular inhibitors, when used alone (EGFRi, BRAFi, MEKi or ERKi), have yielded disappointing survival benefit. To date, it remains difficult to identify the subset of patients who will meaningfully benefit from EGFR/RAS pathway-targeted therapies, likely due to complex resistance mechanisms. A widely held view is that resistance to targeted therapies is due to pre-existence of rare, drug-resistant mutant cells (subclones) that expand and repopulate the tumor following initial successful treatment leading to permanent, clonal resistance. Recently, however, adaptive mutability (AM) of CRC in response to targeted therapies has been reported as a novel, early resistance mechanism. This hypothesis proposes that blocking critical, hard-wired signaling pathways causes a “stress” reaction characterized by the of genotoxic, reactive oxygen species (ROS) and the suppression of DNA mismatch repair enzymes. These early drug-induced changes effectively cause a sub-clonal, hypermutable state that facilitates the eventual emergence of permanently drug-resistant clones. Microsatellite instability (MSI) and other mutator states (i.e. POLE-mutated tumors) are now known to provide a greater probability of checkpoint inhibitor responses. Thus, we hypothesize that the AM induced by EGFR/RAS pathway inhibitors may lead to rapid, sub-clonal, enhanced mutability, and a higher load of neoantigens producing an “MSI-like” state. This hypermutability, if detectable, would portend the higher likelihood of response to checkpoint inhibitors. Traditional analysis of tumor mutation burden (TMB) by NGS assessment of a cancer gene panel would not likely detect genome-wide sub-clonal TMB (scTMB). Standard TMB assays detect bountiful, clonally-expanded mutations fixed in the tumor from the time of its founding. Conversely, we propose that the mutations resulting from a rapid, drug-induced mutator phenotype will likely be present at low variant allele frequencies (i.e. subclonal) that are below the limit of detection of standard NGS approaches. In this proposal, we will test the hypothesis that scTMB occurs in response to targeted therapies, and can be detected using an ultrasensitive and highly specific genome-wide Duplex DNA sequencing assay as an indicator (biomarker) of a mutator state induced by targeted therapies. We propose that the presence of scTMB would predict responses to checkpoint inhibitors, and suggest a benefit to targeted therapies combined with checkpoint inhibitors. These studies will lead to a better molecular understanding of the newly identified “adaptive mutability” resistance mechanism, and potentially provide a solid rationale for the use of combination targeted- and immune-therapies in biomarker-selected patient subpopulations to improve response.

项目概要/摘要结直肠癌（CRC）是癌症死亡的主要原因，不幸的是，如果早期发现，它是可以治愈的。许多 CRC 肿瘤在诊断时已处于晚期，五年治愈率仍然很低，仅为 20% 当 EGFR/RAS 信号通路通过突变持续激活时，它是 CRC 的强大驱动因素。（KRAS ~40%，BRAF ~10%，NRAS ~5%），但单独使用时靶向分子抑制剂（EGFRi、BRAFi、 MEKi 或 ERKi）的生存获益令人失望，迄今为止，仍很难确定其子集。将从 EGFR/RAS 通路靶向治疗中获益的患者，可能是由于复杂的原因一种广泛持有的观点是，对靶向治疗的耐药性是由于先前存在的。罕见的耐药突变细胞（亚克隆）在最初成功后会在肿瘤中扩增并重新增殖然而，最近，CRC 出现了适应性突变（AM）。据报道，对靶向治疗的反应是一种新颖的早期耐药机制。提出阻断关键的、硬连线的信号通路会导致“应激”反应，其特征是基因毒性、活性氧 (ROS) 和 DNA 错配修复酶的抑制。药物引起的变化有效地导致亚克隆、高突变状态，从而促进最终的出现永久耐药克隆的微卫星不稳定性（MSI）和其他突变状态（即 POLE 突变）现在已知肿瘤）可以提供更大的检查点抑制剂反应概率。 EGFR/RAS 通路抑制剂诱导的 AM 可能导致快速、亚克隆、增强的突变性，产生“MSI 样”状态的新抗原负载较高，如果可检测到，则预示着这种超突变性。对检查点抑制剂产生反应的可能性更高。肿瘤突变负荷（TMB）的传统分析。通过 NGS 评估癌症基因组不太可能检测到全基因组亚克隆 TMB (scTMB)。标准 TMB 检测可检测从肿瘤发生之日起就固定在肿瘤中的大量克隆扩增突变在线下成立时，我们提出突变是由药物诱导的快速突变表型引起的。可能会以低于检测限的低变异等位基因频率（即亚克隆）存在在本提案中，我们将测试 scTMB 发生的假设。靶向治疗，并且可以使用超灵敏和高度特异性的全基因组双链 DNA 进行检测测序测定作为靶向治疗诱导的突变状态的指标（生物标志物）。 scTMB 的存在可以预测对检查点抑制剂的反应，并表明对靶向治疗有好处与检查点抑制剂相结合的疗法将带来更好的分子理解。新发现的“适应性可变性”抵抗机制，并可能为该机制提供坚实的理论基础在生物标志物选择的患者亚群中使用联合靶向和免疫疗法以改善回复。