Maximizing Efficacy of EGFR Inhibitors by Defining Resistance Mechanisms

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），但只有少数患者获益。SCCHN是唯一一种EGFR抑制剂作为常规治疗的一部分，但潜在的敏感性或耐药性机制尚未得到验证的癌症。本提案的总体目标是鉴定和表征SCCHN肿瘤中产生对EGFR抑制剂耐药的基因组改变，并确定逆转耐药的机制策略。该建议的长期目标是确定极有可能对EGFR抑制剂耐药的SCCHN患者亚群。初步数据支持这样的假设：独立于EGFR通路的磷脂酰肌醇3-激酶(PI3K)/AKT通路的激活是EGFR抑制剂原发性耐药的主要机制。我们假设SCCHN中EGFR抑制剂的耐药部分是由于PI3K/AKT通路中继发于基因组改变的AKT激活。该应用程序将识别与EGFR抑制剂耐药性相关的PI3K/AKT通路的基因组改变，并描述这些改变的功能意义。该建议利用了在开始使用EGFR抑制剂进行临床试验治疗之前立即收集的已知最大的SCCHN肿瘤样本库。TaqMan(R) SNP基因分型分析和microwestern阵列是芝加哥大学开发的一项新技术，将用于确定EGFR抑制剂耐药肿瘤是否具有更高频率的PI3K/AKT通路改变和激活。此外，在人体组织中发现的最常见的改变将使用临床前模型进行概括，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抑制剂联合使用是否比单独使用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用EGFR抑制剂和不加EGFR抑制剂进行表征。相互作用指数将决定联合治疗是增效还是累加。此外，机制的组合效能将被检查。该提案有望确定SCCHN中与EGFR抑制剂耐药相关的分子表型；了解PI3K/AKT通路基因组改变在SCCHN中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进行单药EGFR抑制剂联合或不联合PI3K/AKT抑制剂治疗SCCHN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靶向治疗中获益的患者。该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PI3K/AKT通路改变的致病性研究较少的疾病中探索新的靶向药物。

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.