Tumor Heterogeneity and Acquired Resistance to EGFR Inhibition

肿瘤异质性和对 EGFR 抑制的获得性耐药

基本信息

批准号：
9221977
负责人：
STANLEY R. HAMILTON
金额：
$ 62.39万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-13 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9221977
关键词：
Aftercare Alleles Archives BRAF gene Biological Assay Biological Markers Biological Models Blood Cancer and Leukemia Group B Cells Cetuximab Chemotherapy-Oncologic Procedure Clinic Clinical Clinical Research Clinical Trials Colorectal Cancer Coupled Data Data Set Disease Disease Progression Ecology Eligibility Determination Emulsions Environment Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Equilibrium Evolution Formalin Frequencies Genes Genomics Healthcare Systems Heterogeneity Individual KRAS2 gene Karyotype determination procedure Label Lentivirus Vector Longitudinal cohort Malignant Neoplasms Methodology Minor Modeling Monitor Monoclonal Antibodies Monoclonal Antibody Therapy Mus Mutation National Cancer Institute of Canada Clinical Trials Group Neoplasm Metastasis Outcome Paraffin Embedding Patient Selection Patient-Focused Outcomes Patients Plasma Population Primary Neoplasm Prospective Studies Randomized Receptor Inhibition Reporting Resistance Retreatment Role Sampling Sampling Studies Savings Southwest Oncology Group Techniques Technology Testing Time Tissues Validation Withdrawal Xenograft Model Xenograft procedure base bevacizumab cell free DNA chemotherapy cohort colon cancer patients cost digital effective therapy improved improved outcome metastatic colorectal mutant mutational status neoplastic cell novel novel strategies predictive marker pressure prospective public health relevance randomized trial resistance mechanism response secondary analysis standard of care targeted treatment therapy duration tumor tumor DNA tumor heterogeneity

项目摘要

DESCRIPTION (provided by applicant): It is increasingly apparent that cancer is a heterogeneous disease with a spectrum of mutations present in individual minor clones that aren't represented in the bulk of the tumor cells. The overall hypothesis is that tumor heterogeneity has important clinical implications for treatment sensitivity and acquired resistance to targeted therapies, using EGFR inhibitors in colorectal cancer as a model system. The introduction of more sophisticated techniques for gene sequencing has made possible the identification of low frequency mutations that were missed with standard sequencing techniques. As KRAS mutations represent a well-recognized and clinically utilized predictive biomarker, it represents an opportunity to explore the implications of KRAS heterogeneity in the setting of EGFR monoclonal antibody (mAb) therapy. Recently, we and others have shown that the presence of low frequency KRAS mutations has been detected in tissue from approximately 15% of metastatic colorectal cancer (mCRC) patients when high-sensitivity sequencing is utilized. These rare KRAS mutant cells are present in what are usually identified as KRAS wild type tumor by less sensitive standard-of-care testing methodologies currently used in the clinic, thereby leading to the hypothesis that these clones are rapidly selected under treatment pressure, resulting in clinical progression to treatment. Retrospective, nonrandomized datasets support this hypothesis; these low-frequency KRAS mutations have been correlated with resistance to anti-EGFR treatment. Specifically, further selection of patients eligible for EGFR mAb therapy would reduce the cost of such therapies to the health care system (with modeled savings of $200 million per year given the prospective identification of 25% of non-responding patients). In this proposal we hypothesize that treatment-induced clonal changes are a "dynamic balance" in a heterogeneous tumor population. We propose to evaluate tumor genetic changes by studying samples from large randomized trials, including the primary tumor and circulating free tumor DNA (cfDNA) obtained from patient plasma samples. To capture longer-term dynamics, we will apply these monitoring techniques to a longitudinal cohort with an embedded prospective clinical trial of anti-EGFR retreatment. Patient-derived murine xenograft models will be utilized to more precisely quantify tumor dynamics. Understand the mechanisms of resistance of CRC will require a more detailed understanding of the heterogeneity and temporal dynamics of genomic changes, thereby leading to improved biomarkers for benefit and novel strategies to re-challenge tumors with previously effective therapy.

描述（由申请人提供）：越来越明显的是，癌症是一种异质性疾病，在单个次要克隆中存在一系列突变，而这些疾病在大部分肿瘤细胞中并未表示。总体假设是，肿瘤异质性对治疗敏感性具有重要的临床意义，并使用大肠癌中的EGFR抑制剂作为模型系统，对靶向疗法产生了对靶向疗法的耐药性。引入更复杂的基因测序技术已使使用标准测序技术错过的低频突变的鉴定。由于KRAS突变代表了一种公认且临床上使用的预测性生物标志物，因此它代表了探索KRAS异质性在EGFR单克隆抗体（MAB）治疗环境中的含义的机会。最近，我们和其他人表明，当使用高敏化测序时，已经在大约15％的转移性结直肠癌（MCRC）患者的组织中检测到低频KRAS突变的存在。这些罕见的KRAS突变细胞存在于通常被诊断中使用的较不敏感的标准测试方法中，通常被鉴定为KRAS野生型肿瘤，从而导致假设这些克隆在治疗压力下迅速选择，从而导致临床进展到治疗。回顾性非随机数据集支持这一假设；这些低频KRAS突变与对抗EGFR治疗的抗性有关。具体而言，进一步选择有资格获得EGFR MAB治疗的患者将降低此类疗法的卫生保健系统成本（鉴于预期鉴定了25％的非反应患者，每年的储蓄每年为2亿美元）。在此提案中，我们假设治疗引起的克隆变化是异质肿瘤种群中的“动态平衡”。我们建议通过研究来自大型随机试验的样品，包括原发性肿瘤和循环自由肿瘤DNA（CFDNA）来评估肿瘤遗传变化。为了捕获长期动态，我们将使用嵌入式抗EGFR撤退的前瞻性临床试验应用这些监测技术。患者衍生的鼠异种移植模型将用于更精确地量化肿瘤动力学。了解CRC耐药性的机制将需要对基因组变化的异质性和时间动力学有更详细的了解，从而改善生物标志物，从而通过以前有效的治疗来重新挑战肿瘤，以获得益处和新型策略。