Evolution of resistance of EGFR mutant non-small cell lung cancer

EGFR突变非小细胞肺癌耐药演变

• 批准号: 9243548
• 负责人: Aaron N Hata
• 金额: $ 17.93万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-14 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9243548
• 关键词: Affect; Aftercare; Apoptotic; Bioinformatics; Biopsy Specimen; Cancer Center; Cell Culture Techniques; Cell Line; Cells; Cellular Stress Response; Characteristics; Clinic; Clinical; Clinical effectiveness; Clonal Evolution; Communities; Development; Development Plans; Disease Progression; Drug Combinations; Drug Targeting; Effectiveness; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Epigenetic Process; Event; Evolution; Faculty; Future; Gatekeeping; General Hospitals; Generations; Genetic; Genomics; Hematology; Induced Mutation; K-Series Research Career Programs; Laboratories; Lead; Malignant Neoplasms; Malignant neoplasm of lung; Massachusetts; Medicine; Mentors; Mentorship; Modeling; Molecular; Mutation; NCI Center for Cancer Research; Nature; Non-Small-Cell Lung Carcinoma; Oncogenic; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacotherapy; Play; Pleural effusion disorder; Preclinical Drug Evaluation; Process; Pulmonology; Receptor Inhibition; Records; Research; Research Personnel; Research Support; Resistance; Resistance development; Resources; Role; Sampling; Scientist; Signal Pathway; Signal Transduction; Therapeutic; Thoracic Oncology; Time; Training Programs; Training Support; United States National Institutes of Health; Ursidae Family; Work; abstracting; acquired drug resistance; anticancer research; cancer cell; career development; design; effective therapy; genetic signature; improved; in vitro Model; in vivo; ineffective therapies; insight; instructor; interest; medical schools; member; mutant; neoplastic cell; novel; novel therapeutics; oncology; prevent; programs; research study; resistance mechanism; response; skills; small hairpin RNA; small molecule; targeted treatment; transcriptome sequencing; treatment strategy; tumor

NIH Mentored Clinical Scientist Research Career Development Award (K08) Application FOA number: PA-14-046 Project: Evolution of resistance of EGFR mutant non-small cell lung cancer Applicant: Aaron Hata Project Summary/Abstract Advances in our understanding of the genetic alterations in cancer have given rise to effective therapies that target specific oncogenic signaling pathways. For instance, treatment of non-small cell lung cancers (NSCLCs) harboring activating mutations in the epidermal growth factor receptor (EGFR) with small molecule EGFR inhibitors leads to dramatic clinical responses. Unfortunately, the clinical effectiveness of targeted therapies is limited by the inevitable emergence of acquired drug resistance that ultimately renders the therapy ineffective. Understanding these mechanisms of resistance is fundamental to developing improved treatment strategies to improve patient outcomes. In this project, Dr. Hata proposes to study the evolution of acquired resistance of EGFR mutant NSCLC. Dr. Hata is an Instructor in Medicine at Harvard Medical School and a member of the Hematology/Oncology faculty at the Massachusetts General Hospital Cancer Center. As a Hematology/Oncology Fellow in the Dana Farber/Partners CancerCare Oncology Training program, Dr. Hata joined the laboratory of Dr. Jeffrey Engelman in the MGH Center for Cancer Research in 2010, where he has focused on understanding how changes in apoptotic signaling affect sensitivity and resistance to targeted therapies. Since joining the MGH faculty in 2013, Dr. Hata has continued his research studies in the Engelman Laboratory, and is now interested in applying insights gained from his prior work toward understanding how EGFR mutant NSCLC resistant clones emerge and evolve during therapy. Dr. Hata recently demonstrated that genetic mechanisms of resistance such as the EGFRT790M mutation can evolve de novo from surviving drug tolerant cells during drug treatment, suggesting that drug tolerant cells that do not yet harbor genetic mechanisms of resistance can serve as an important reservoir for subsequent evolution of resistance. In this project, Dr. Hata proposes to investigate the evolution of acquired resistance of EGFR mutant NSCLC to EGFR inhibitors in patients. Examining tumor biopsy specimens from patients at the time of disease progression for genetic signatures that accumulate in drug tolerant cells, he will determine whether resistant cancers derived from pre-existing resistant sub-clones or evolved during therapy. He will integrate analysis of tumor cells from patients undergoing EGFR inhibitor therapy with functional studies using laboratory tumor models derived from these same patients to characterize drug tolerant tumor cells in vivo. Finally, he will investigate novel drug treatment strategies designed to target drug tolerant cells in vivo. These studies will significantly enhance our understanding of how acquired drug resistance evolves in the clinic and identify novel treatment strategies that delay or prevent emergence of resistance. To accomplish these studies, Dr. Hata will leverage the research and clinical resources of the Engelman Lab, the MGH Cancer Center and the larger Dana Farber/Harvard Cancer Center community. Under the primary mentorship of Dr. Engelman, he will collaborate closely with experts in the field of genomics and epigenetics, as well as clinicians within the MGH Thoracic Oncology and Interventional Pulmonology groups. To oversee his scientific and career development, he has established a mentoring committee of both internal and external faculty who have extensive expertise in basic and translational oncology and proven track records of mentoring junior faculty during the transition to independence. He has created a career development plan designed to facilitate development of specific skills in genomics and bioinformatics that will enable him to be a successful independent investigator. This project will lead to novel insights into the evolution of acquired resistance to EGFR inhibitors in NSCLC as well as resistance to targeted therapies in general, and will inform future treatment strategies designed to delay or prevent acquired resistance in the clinic. Additionally, this project will provide critical research and training support for Dr. Hata as he establishes himself as an independent investigator in the field of translational lung cancer research. !

美国国立卫生研究院临床科学家导师研究职业发展奖(K08)申请 FOA编号：PA-14-046 项目：EGFR突变型非小细胞肺癌耐药性的演变 申请人：Aaron Hata 项目摘要/摘要 我们对癌症基因改变的理解的进步催生了有效的治疗方法。 以特定的致癌信号通路为靶点。例如，非小细胞肺癌的治疗 (NSCLC)表皮生长因子受体(EGFR)小分子激活突变 EGFR抑制剂可导致显著的临床反应。不幸的是，靶向治疗的临床疗效 治疗受到不可避免的获得性耐药性的出现的限制，最终导致治疗 效果不佳。了解这些耐药机制是开发改进治疗方法的基础 改善患者预后的策略。 在这个项目中，Hata博士建议研究EGFR突变NSCLC获得性耐药性的进化。Dr。 Hata是哈佛医学院的医学讲师，也是血液学/肿瘤学教员 在马萨诸塞州总医院癌症中心。作为DANA的血液学/肿瘤学研究员 Farber/Partners CancerCare肿瘤学培训计划，Hata博士加入了Jeffrey博士的实验室 2010年，Engelman在MGH癌症研究中心工作，在那里他专注于了解 细胞凋亡信号的改变会影响靶向治疗的敏感性和耐药性。自加入MGH以来 2013年，Hata博士在恩格尔曼实验室继续他的研究学习，现在有兴趣 在应用他之前工作中获得的见解来理解EGFR突变体NSCLC是如何抵抗的 克隆人在治疗过程中不断涌现和进化。 Hata博士最近证明了耐药性的遗传机制，如EGFRT790M突变 可以在药物治疗期间从存活的耐药细胞进化而来，这表明耐药细胞 尚不具有抗性遗传机制的菌株可以作为后续的重要储存库 抵抗力的演变。在这个项目中，Hata博士建议研究获得性抗药性的演变 患者中EGFR突变的非小细胞肺癌患者转为EGFR抑制剂。在医院检查患者的肿瘤活检标本 他将确定在耐药细胞中积累的基因特征的疾病进展时间 耐药癌症是否起源于先前存在的耐药亚克隆或在治疗过程中进化。他会的 对接受EGFR抑制剂治疗的患者的肿瘤细胞与功能研究的综合分析 从这些患者衍生的实验室肿瘤模型来表征体内耐药的肿瘤细胞。 最后，他将研究针对体内耐药细胞的新型药物治疗策略。这些 研究将大大加强我们对获得性耐药在临床和临床上如何演变的理解 确定延缓或防止耐药性出现的新的治疗策略。 为了完成这些研究，Hata博士将利用Engelman的研究和临床资源 实验室、MGH癌症中心和更大的Dana Farber/哈佛癌症中心社区。在.之下 作为恩格尔曼博士的主要导师，他将与基因组学领域的专家和 表观遗传学，以及MGH胸科肿瘤学和介入性肺病学小组的临床医生。 为了监督他的科学和事业发展，他成立了一个由两个内部人员组成的指导委员会 和外部教员，他们在基础肿瘤学和转化性肿瘤学方面拥有广泛的专业知识，并有可靠的记录 在过渡到独立的过程中指导初级教员。他制定了一份职业发展计划 旨在促进基因组学和生物信息学方面的特定技能的发展，使他能够成为一名 成功的独立调查员。 该项目将导致对获得性EGFR抑制剂耐药性的演变有新的见解 NSCLC以及对靶向治疗的耐药性，并将告知未来的治疗策略 用于延缓或防止临床中的后天抵抗力。此外，该项目将提供关键的 为Hata博士提供研究和培训支持，因为他在该领域确立了自己的独立调查员地位 转化型肺癌研究。 好了！