Impact of heterogeneity on response to EGFR T790M inhibitors

异质性对 EGFR T790M 抑制剂反应的影响

• 批准号: 8887518
• 负责人: Jeffrey A. Engelman
• 金额: $ 40.62万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8887518
• 关键词: Anatomy; Autopsy; Biological Markers; Biopsy; Biopsy Specimen; Cancer Patient; Cell Line; Cells; Classification; Clinic; Clinical; Clinical Research; Clinical Trials; Clone Cells; Coupled; Data; Development; Disease; Disease remission; Enrollment; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erlotinib; Face; Future; Gatekeeping; Gefitinib; Generations; Genotype; Heterogeneity; In Vitro; Individual; Investigation; Laboratories; Laboratory Study; Lead; Learning; Lesion; Location; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Mediating; Methods; Modeling; Molecular; Mutation; Non-Small-Cell Lung Carcinoma; Outcome; Patients; Preclinical Drug Evaluation; Quality of life; Regimen; Resistance; Resistance development; Sampling; Signal Transduction; Site; Specimen; Techniques; Testing; Therapeutic; Translational Research; Treatment outcome; Tumor-Derived; Tyrosine Kinase Inhibitor; base; cancer cell; cell free DNA; combat; design; drug efficacy; improved; in vivo; inhibitor/antagonist; insight; mutant; new technology; next generation; novel; novel diagnostics; phase I trial; programs; public health relevance; resistance mechanism; resistance mutation; response; standard of care; targeted treatment; treatment strategy; tumor; tumor DNA

 DESCRIPTION (provided by applicant): The genotype-directed use of EGFR TKIs in EGFR-mutant lung cancer patients has fundamentally changed the face of the disease with improved response to therapy, preserved quality of life, and prolonged progression-free and overall survival. However, tumors that initially respond acquire resistance after about 1 year. In 50-60% of cases, resistance is mediated by the T790M resistance mutation in the gatekeeper location. However, we now appreciate that it may be overly simplistic to categorize cancers in a binary fashion such as T790M "positive" or "negative". We have observed that within an individual patient there exist intra- tumoral and inter-tumoral heterogeneity with respect to T790M. Importantly, novel T790M-specific "3rd- generation" EGFR inhibitors are currently entering the clinic and have shown significant activity in phase I trials for patients whose tumors harbor T790M. We have also learned that a subset of T790M positive cancers are intrinsically resistant to T790M inhibitors because they are no longer solely reliant on EGFR signaling for their viability. Thus, there is an increasing urgency to understand T790M heterogeneity, intrinsic resistance and their implications on patient response to these new therapies. In this proposal, we will tackle two aspects limiting the efficacy to 3rd generation EGFR TKIs; clonal heterogeneity and intrinsic lack of sensitivity. We will comprehensively explore clonal T790M heterogeneity in EGFR-mutant cancers with acquired resistance to the initial EGFR TKIs, and expand on our Preliminary Data suggesting that the amount of heterogeneity impacts response to 3rd-generation EGFR inhibitors. Utilizing cell lines derived directly from patient biopsies, we will also design and test therapeutic strategies to improve treatment outcomes in tumors that are inherently resistant to 3rd-generation TKIs. This study should lay the groundwork for newer diagnostic and treatment paradigms that assess, combat and overcome the complexities of targeted therapy resistance so patients can enjoy long-term remissions or even cures. Specific Aim 1: Define the intra- and inter-tumoral heterogeneity of T790M clones in cancers with acquired resistance to EGFR TKIs Specific Aim 2: Determine if T790M heterogeneity predicts responsiveness to 3rd generation EGFR inhibitors. Specific Aim 3: Identify therapeutic strategies for T790M cancers with intrinsic resistance to 3rd generation EGFR inhibitors.

 描述（由适用提供）：EGFR TKI在EGFR突变肺癌患者中的基因型定向使用，从根本上改变了对疾病的面貌，对治疗的反应改善，保留的生活质量以及长时间的无进展和整体生存率。但是，大约1年后最初对收购抵抗作出反应的肿瘤。在50-60％的病例中，电阻是由T790M电阻突变介导的。但是，我们现在感谢以二进制方式对癌症进行分类可能过于简单，例如T790M“正”或“负”。我们已经观察到，在单个患者中存在相对于T790M的肿瘤内和肿瘤间异质性。重要的是，新型T790M特异性的“第三代” EGFR抑制剂目前正在进入诊所，并在I期试验中显示出对肿瘤含有T790M的患者的重要活性。我们还了解到，T790M阳性癌症的一部分在本质上对T790M抑制剂具有抗性，因为它们不再仅对EGFR信号的生存能力敏感。这就是了解T790M的异质性，内在抗药性及其对患者对这些新疗法的反应的影响，越来越紧迫。在此提案中，我们将解决将效率限制在第三代EGFR TKIS的两个方面。克隆异质性和内在缺乏灵敏度。我们将全面探索具有对初始EGFR TKIS的耐药性的EGFR突变癌中克隆T790M的异质性，并根据我们的初步数据扩展了异质性的量影响第三代EGFR抑制剂的反应。利用直接从患者活检中得出的细胞系，我们还将设计和测试疗法策略，以改善对第三代TKIS固有抗性的肿瘤的治疗结果。这项研究应为较新的诊断和治疗范式奠定基础，以评估，战斗和克服靶向治疗的复杂性，以便患者可以长期减免甚至治愈。具体目的1：定义具有对EGFR TKIS特定目标的抗性癌症中T790M克隆的肿瘤内和肿瘤间异质性2：确定T790M异质性预测是否对第三代EGFR抑制剂的响应能力是否响应。特定目的3：确定对第三代EGFR抑制剂具有内在抗性的T790M癌症的治疗策略。