Maximizing Efficacy of EGFR Inhibitors by Defining Resistance Mechanisms

通过定义耐药机制最大化 EGFR 抑制剂的功效

基本信息

批准号：
8530212
负责人：
Ezra Cohen
金额：
$ 18.96万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-15 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8530212
关键词：
1-Phosphatidylinositol 3-Kinase Biological Assay Chicago Clinical Clinical Trials Combined Modality Therapy Data Disease Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Epigenetic Process Freezing Frequencies Genomics Goals Head and Neck Cancer Head and Neck Neoplasms Head and Neck Squamous Cell Carcinoma Health Human In Vitro Lead Link Malignant Neoplasms Methods Minority Mission Molecular Mutation Outcome Pathogenicity Pathway interactions Patients Pharmaceutical Preparations Pre-Clinical Model Proto-Oncogene Proteins c-akt Public Health Recurrence Research Resistance SNP genotyping Sampling Secondary to Signal Transduction Squamous cell carcinoma Therapeutic Therapeutic Agents Therapeutic Intervention Therapy Clinical Trials Translating Universities combinatorial human tissue improved in vivo indexing inhibitor/antagonist innovation molecular phenotype new technology novel public health relevance receptor expression repository resistance mechanism response standard of care tumor

1-Phosphatidylinositol 3-Kinase Biological Assay Chicago Clinical Clinical Trials Combined Modality Therapy Data Disease Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Epigenetic Process Freezing Frequencies Genomics Goals Head and Neck Cancer Head and Neck Neoplasms Head and Neck Squamous Cell Carcinoma Health Human In Vitro Lead Link Malignant Neoplasms Methods Minority Mission Molecular Mutation Outcome Pathogenicity Pathway interactions Patients Pharmaceutical Preparations Pre-Clinical Model Proto-Oncogene Proteins c-akt Public Health Recurrence Research Resistance SNP genotyping Sampling Secondary to Signal Transduction Squamous cell carcinoma Therapeutic Therapeutic Agents Therapeutic Intervention Therapy Clinical Trials Translating Universities combinatorial human tissue improved in vivo indexing inhibitor/antagonist innovation molecular phenotype new technology novel public health relevance receptor expression repository resistance mechanism response standard of care tumor

展开

项目摘要

DESCRIPTION (provided by applicant): Epidermal growth factor receptor (EGFR) inhibitors are commonly used in squamous cell carcinoma of the head and neck (SCCHN) but only a minority of patients derives benefit. SCCHN is the only cancer where EGFR inhibitors are part of routine management but mechanisms underlying sensitivity or resistance are not validated. The overall objectives in this proposal are to identify and characterize genomic alterations in SCCHN tumors that produce resistance to EGFR inhibitors as well as define mechanistic strategies to reverse resistance. The long-term goal of this proposal is to identify a subset of SCCHN patients that are highly likely to be resistant to EGFR inhibitors. Preliminary data support the hypothesis that activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, independent of the EGFR pathway, is a major mechanism of primary resistance to EGFR inhibitors. We hypothesize that EGFR inhibitor resistance in SCCHN is due in part to activation of AKT secondary to genomic alterations in the PI3K/AKT pathway. This application will identify genomic alterations in the PI3K/AKT pathway associated with resistance to EGFR inhibitors and characterize the functional significance of these alterations. This proposal takes advantage of the largest known repositories of SCCHN tumor samples collected immediately prior to initiating clinical trial therapy with an EGFR inhibitor. TaqMan(R) SNP Genotyping Assay and microwestern arrays, a novel technology developed at University of Chicago, will be used to determine if EGFR inhibitor resistant tumors harbor a higher frequency of PI3K/AKT pathway alterations and activation. Furthermore, the most common alterations found in human tissues will be recapitulated using preclinical models to determine the phenotypic and mechanistic changes associated with each. In addition, this application will determine whether the combination of PI3K/AKT and EGFR inhibitors are more effective than either agent alone in SCCHN preclinical models and identify the mechanistic underpinnings of efficacy. The activity of two distinct PI3K/AKT inhibitors will be characterized with and without EGFR inhibitors in vitro and in vivo. An interaction index will determine whether combination therapy is synergistic or additive. Furthermore, the mechanisms underlying combinatorial efficacy will be examined. This proposal is expected to define a molecular phenotype associated with resistance to EGFR inhibitors in SCCHN; understand the functional significance and therapeutic implications of PI3K/AKT pathway genomic alterations in SCCHN; and provide critical rationale to begin clinical trials and select appropriate patients for therapy with single-agent EGFR inhibitors with or without PI3K/AKT inhibitors in SCCHN. The impact of this proposal will be to fundamentally alter the way SCCHN patients are treated by determining those that are unlikely to benefit from EGFR targeted therapy. This proposal applies hypothesis-driven, innovative molecular methods to an unparalleled tumor sample set and explores novel targeted agents in a disease where research on the pathogenicity of PI3K/AKT pathway alterations has been sparse.

描述（由申请人提供）：表皮生长因子受体（EGFR）抑制剂通常用于头颈部鳞状细胞癌（SCCHN），但只有少数患者获得了益处。 SCCHN是唯一的EGFR抑制剂是常规管理的一部分，但未验证敏感性或耐药性的机制。该提案中的总体目标是识别和表征SCCHN肿瘤中产生抗EGFR抑制剂的基因组改变，并定义了逆向抗性的机械策略。该提案的长期目标是确定一部分SCCHN患者，这些患者极有可能对EGFR抑制剂具有抗性。初步数据支持以下假设：磷脂酰肌醇3-激酶（PI3K）/AKT途径（独立于EGFR途径）是对EGFR抑制剂的主要抗性的主要机制。我们假设SCCHN中的EGFR抑制剂耐药性部分归因于PI3K/AKT途径中基因组改变的Akt激活。该应用将确定与对EGFR抑制剂抗性有关的PI3K/AKT途径中的基因组改变，并表征了这些改变的功能意义。该建议利用了在使用EGFR抑制剂开始临床试验疗法之前收集的SCCHN肿瘤样品最大的已知存储库。 Taqman（R）SNP基因分型测定法和芝加哥大学开发的新技术将用于确定EGFR抑制剂耐药性肿瘤是否具有更高的PI3K/AKT途径变化和激活的频率。此外，将使用临床前模型概括在人体组织中发现的最常见变化，以确定与每个模型相关的表型和机械变化。此外，该应用将确定PI3K/AKT和EGFR抑制剂的组合是否比SCCHN临床前模型中的任何一种药物更有效，并确定了功效的机械基础。有或没有EGFR抑制剂在体外和体内，两个不同的PI3K/AKT抑制剂的活性将被表征。相互作用指数将确定组合疗法是协同作用还是添加剂。此外，将检查组合功效的基础机制。预计该建议将定义与SCCHN中对EGFR抑制剂抗性相关的分子表型。了解SCCHN中PI3K/AKT途径基因组改变的功能意义和治疗意义；并提供关键的基本原理，以开始临床试验，并选择适当的患者进行SCCHN中有或没有PI3K/AKT抑制剂的单药EGFR抑制剂的治疗。该提案的影响将是从根本上改变SCCHN患者的治疗方式，通过确定不太可能受益于EGFR靶向疗法的患者的治疗方式。该提案将假设驱动的创新分子方法应用于无与伦比的肿瘤样品集，并探索了一种疾病中的新型靶向药物，在这种疾病中，对PI3K/AKT途径改变的致病性的研究很少。