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

• 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
• 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

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）抑制剂常用于治疗头颈鳞状细胞癌（SCCHN），但只有少数患者受益。 SCCHN 是唯一一种将 EGFR 抑制剂纳入常规治疗但其敏感性或耐药性机制尚未得到验证的癌症。该提案的总体目标是识别和表征 SCCHN 肿瘤中产生对 EGFR 抑制剂耐药性的基因组改变，并定义逆转耐药性的机制策略。该提案的长期目标是确定极有可能对 EGFR 抑制剂产生耐药性的 SCCHN 患者子集。初步数据支持这样的假设：磷脂酰肌醇 3 激酶 (PI3K)/AKT 途径的激活独立于 EGFR 途径，是对 EGFR 抑制剂原发耐药的主要机制。我们假设 SCCHN 中的 EGFR 抑制剂耐药性部分是由于 PI3K/AKT 通路基因组改变继发的 AKT 激活。该应用将鉴定与 EGFR 抑制剂耐药相关的 PI3K/AKT 通路中的基因组改变，并表征这些改变的功能意义。该提案利用了在开始使用 EGFR 抑制剂进行临床试验治疗之前收集的最大的已知 SCCHN 肿瘤样本存储库。 TaqMan(R) SNP 基因分型测定和 microwestern 阵列是芝加哥大学开发的一项新技术，将用于确定 EGFR 抑制剂耐药性肿瘤是否具有更高频率的 PI3K/AKT 通路改变和激活。此外，将使用临床前模型来概括在人体组织中发现的最常见的改变，以确定与每种改变相关的表型和机制变化。此外，该应用将确定在 SCCHN 临床前模型中 PI3K/AKT 和 EGFR 抑制剂的组合是否比单独使用任一药物更有效，并确定疗效的机制基础。两种不同 PI3K/AKT 抑制剂的活性将在体外和体内表征有和没有 EGFR 抑制剂的情况。相互作用指数将确定联合治疗是协同的还是相加的。此外，还将研究组合功效的潜在机制。该提案预计将定义与 SCCHN EGFR 抑制剂耐药性相关的分子表型；了解 SCCHN 中 PI3K/AKT 通路基因组改变的功能意义和治疗意义；并为开始临床试验和选择合适的患者在 SCCHN 中使用单药 EGFR 抑制剂联合或不联合 PI3K/AKT 抑制剂治疗提供关键依据。该提案的影响将从根本上改变 SCCHN 患者的治疗方式，确定那些不太可能从 EGFR 靶向治疗中受益的患者。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本集，并探索针对 PI3K/AKT 通路改变致病性研究很少的疾病的新型靶向药物。