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: 9762863
• 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/9762863
• 关键词: Affect; Apoptotic; Bioinformatics; Biopsy Specimen; Cancer Center; Cell Culture Techniques; Cell Line; Cells; Cellular Stress Response; Characteristics; Clinic; Clinical; Clinical effectiveness; Clonal Evolution; Development; Development Plans; Disease Progression; Drug Combinations; Drug Screening; Drug Targeting; Drug Tolerance; Effectiveness; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Epigenetic Process; Event; Evolution; Faculty; Future; Gatekeeping; General Hospitals; Generations; Genetic; Genetic Transcription; Genomics; Hematology; Induced Mutation; Intervention; K-Series Research Career Programs; Laboratories; 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; Pharmacotherapy; Play; Pleural effusion disorder; 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; acquired drug resistance; anticancer research; cancer cell; career development; community center; 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; single-cell RNA sequencing; skills; small hairpin RNA; small molecule; targeted treatment; 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. !

NIH指导的临床科学家研究职业发展奖（K08）应用程序 FOA编号：PA-14-046 项目：EGFR突变非小细胞肺癌的抵抗力的演变 申请人：亚伦·哈塔（Aaron Hata） 项目摘要/摘要 我们对癌症遗传改变的理解的进步已导致有效的疗法 该目标特定的致癌信号通路。例如，治疗非小细胞肺癌 （NSCLC）用小分子携带表皮生长因子受体（EGFR）中的激活突变 EGFR抑制剂会导致急剧的临床反应。不幸的是，目标的临床有效性 疗法受到获得的耐药性抗性的不可避免的限制，该耐药性最终导致治疗 无效。了解这些抗药性机制对于发展改进的治疗至关重要 改善患者预后的策略。 在这个项目中，HATA博士建议研究EGFR突变体NSCLC获得的抗性的演变。博士 哈塔（Hata 在马萨诸塞州综合医院癌症中心。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 恩格尔曼（Engelman 凋亡信号传导的变化会影响敏感性和对靶向疗法的抗性。自加入MGH以来 2013年的教师Hata博士继续在恩格曼实验室进行研究，现在很感兴趣 在运用从他先前的工作中获得的见解来了解EGFR突变体NSCLC如何抗性 克隆在治疗过程中出现和进化。 HATA博士最近证明了抗药性的遗传机制，例如EGFRT790M突变 可以在药物治疗期间从幸存的药物耐受细胞中发展起来，这表明药物耐药细胞 尚无抗药性的遗传机制可以作为随后的重要储层 抵抗的演变。在这个项目中，Hata博士建议调查获得的抗药性的演变 EGFR突变NSCLC至患者的EGFR抑制剂。检查来自患者的肿瘤活检标本 在药物耐受细胞中积累的遗传特征的疾病进展时间，他将确定 无论是源自先前存在的抗性亚c-Clones还是在治疗过程中进化的抗性癌症。他会的 将接受EGFR抑制剂疗法的患者的肿瘤细胞与功能研究进行整合 实验室肿瘤模型从这些相同患者中得出，以表征体内药物耐受性肿瘤细胞。 最后，他将研究旨在靶向体内药物耐受细胞的新型药物治疗策略。这些 研究将显着增强我们对诊所中获得的耐药性如何发展的理解和 确定延迟或防止抗药性出现的新型治疗策略。 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/Harvard Cancer Center社区。在 恩格曼博士的主要指导，他将与基因组学领域的专家紧密合作 MGH胸部肿瘤学和介入肺病学组中的表观遗传学以及临床医生。 为了监督他的科学和职业发展，他成立了一个内部的指导委员会 以及在基本和翻译肿瘤学领域拥有广泛专业知识和经过验证的往绩记录的外部教师 在过渡到独立期间指导初级教师的指导。他制定了职业发展计划 旨在促进基因组学和生物信息学方面的特定技能的发展，使他成为一个 成功的独立研究员。 该项目将导致对获得对EGFR抑制剂的抗性演变的新见解 NSCLC以及对靶向疗法的抵抗，并将为未来的治疗策略提供信息 旨在延迟或防止诊所获得的抗药性。此外，该项目将提供关键 HATA博士在该领域担任独立研究员时，对Hata博士的研究和培训支持 翻译肺癌研究。 呢