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

NIH指导临床科学家研究职业发展奖（K 08）申请 FOA编号：PA-14-046 项目：EGFR突变型非小细胞肺癌耐药的演变 申请人：Aaron Hata 项目概要/摘要 我们对癌症遗传变异的理解的进步已经产生了有效的治疗方法 针对特定的致癌信号通路。例如，非小细胞肺癌的治疗 在表皮生长因子受体（EGFR）中含有小分子激活突变的NSCLC EGFR抑制剂导致戏剧性的临床反应。不幸的是，靶向治疗的临床效果 获得性耐药性的不可避免的出现限制了治疗， 无效。了解这些耐药机制对于开发更好的治疗方法至关重要 改善患者预后的策略。 在该项目中，Hata博士建议研究EGFR突变型NSCLC获得性耐药的演变。博士 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 Engelman于2010年在MGH癌症研究中心，在那里他专注于了解如何 凋亡信号的变化影响对靶向治疗的敏感性和抗性。自从加入MGH 2013年，Hata博士继续在Engelman实验室进行研究，现在对 在应用从他先前的工作中获得的见解来理解EGFR突变型NSCLC耐药 克隆人在治疗过程中出现并进化。 Hata博士最近证明，耐药的遗传机制，如EGFRT 790 M突变， 可以在药物治疗期间从存活的药物耐受细胞重新进化，这表明药物耐受细胞 尚未具有抗性遗传机制的基因可以作为后续抗性的重要储存库。 抵抗力的进化。在这个项目中，Hata博士建议研究获得性耐药性的演变， EGFR突变型NSCLC患者对EGFR抑制剂的耐受性。检查来自患者的肿瘤活检标本， 他将确定在耐药细胞中积累的遗传标记的疾病进展时间， 无论耐药癌症是源自预先存在的耐药亚克隆还是在治疗过程中进化而来。他将 来自接受EGFR抑制剂治疗患者的肿瘤细胞的整合分析与使用 来自这些相同患者的实验室肿瘤模型，以在体内表征药物耐受性肿瘤细胞。 最后，他将研究旨在靶向体内耐药细胞的新型药物治疗策略。这些 这些研究将大大提高我们对获得性耐药性在临床上如何演变的理解， 确定新的治疗策略，延迟或防止耐药性的出现。 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癌症中心和更大的达纳法伯/哈佛癌症中心社区。下 作为Engelman博士的主要导师，他将与基因组学领域的专家密切合作， 表观遗传学，以及MGH胸部肿瘤和介入肺病组的临床医生。 为了监督他的科学和职业发展，他建立了一个内部和内部的指导委员会。 以及在基础和转化肿瘤学方面拥有广泛专业知识并有良好记录的外部教师 在向独立过渡的过程中指导初级教师。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具体技能的发展，使他能够成为一名 成功的独立调查员 该项目将导致对EGFR抑制剂获得性耐药性演变的新见解， NSCLC以及对靶向治疗的耐药性，并将为未来的治疗策略提供信息 旨在延缓或预防临床获得性耐药性。此外，该项目将提供关键的 为Hata博士提供研究和培训支持，使他成为该领域的独立研究者 转化型肺癌研究的一部分。 !

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. !