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: 8385420
• 负责人: Ezra Cohen
• 金额: $ 23.7万
• 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/8385420
• 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; 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. PUBLIC HEALTH RELEVANCE: This proposal is relevant to public health because squamous cell carcinoma of the head and neck is the 5th most common cancer worldwide and determining mechanisms of resistance to one of the most widely used class of therapeutic agents in this disease, epidermal growth factor receptor inhibitors, will ultimately improve survival. The proposed research is relevant to the NIH's mission in general and to NIDCR's specifically because it will reduce the burdens on human health caused by head and neck cancer.

描述(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)，但只有少数患者受益。SCCHN是唯一一种将EGFR抑制剂作为常规治疗的一部分，但其敏感性或耐药性的潜在机制尚未得到验证的癌症。这项提案的总体目标是识别和表征SCCHN肿瘤中产生对EGFR抑制剂耐药的基因组变化，并定义逆转耐药的机制策略。这项建议的长期目标是确定SCCHN患者中极有可能对EGFR抑制剂耐药的子集。初步数据支持磷脂酰肌醇3-激酶(PI3K)/AKT通路的激活是原发性耐药的主要机制，该通路独立于EGFR通路。我们推测，在SCCHN中，EGFR抑制剂耐药性的部分原因是PI3K/AKT通路的基因组改变继发于AKT的激活。这一应用将识别与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。这项建议利用了已知的最大规模的SCCHN肿瘤样本储存库，这些样本是在启动EGFR抑制剂的临床试验治疗之前立即收集的。芝加哥大学开发的一项新技术TaqMan(R)SNP基因分型分析和微蛋白质阵列将用于确定耐EGFR抑制剂的肿瘤是否存在更高频率的PI3K/AKT途径改变和激活。此外，在人类组织中发现的最常见的变化将使用临床前模型来概括，以确定与每种变化相关的表型和机制变化。此外，这项应用将确定在SCCHN临床前模型中，PI3K/AKT和EGFR抑制剂联合使用是否比任何一种药物更有效，并确定疗效的机制基础。两种不同的PI3K/AKT抑制剂的活性将在体外和体内表征有无EGFR抑制剂。相互作用指数将决定联合疗法是协同疗法还是相加疗法。此外，还将研究组合药效的潜在机制。这项建议有望确定SCCHN中与EGFR抑制剂耐药相关的分子表型；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抑制剂与PI3K/AKT抑制剂的治疗提供关键的理论基础。这项提议的影响将是通过确定那些不太可能从EGFR靶向治疗中受益的患者，从根本上改变SCCHN患者的治疗方式。这项建议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，并在一种疾病中探索新的靶向药物，在这种疾病中，对PI3K/AKT途径改变的致病性研究一直很少。 公共卫生相关性：这项建议与公共健康相关，因为头颈部鳞状细胞癌是世界上第五大最常见的癌症，确定这种疾病中最广泛使用的治疗药物之一--表皮生长因子受体抑制剂--的耐药性机制最终将提高存活率。这项拟议的研究总体上与NIH的任务相关，特别是与NIDCR的任务相关，因为它将减少头颈癌对人类健康造成的负担。