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 指导临床科学家研究职业发展奖 (K08) 申请 FOA 编号：PA-14-046 项目：EGFR突变非小细胞肺癌耐药进化 申请人：亚伦·哈塔 项目概要/摘要 我们对癌症基因改变理解的进步带来了有效的治疗方法 靶向特定的致癌信号通路。例如，非小细胞肺癌的治疗 （NSCLC）在表皮生长因子受体（EGFR）中含有小分子激活突变 EGFR 抑制剂可带来显着的临床反应。不幸的是，靶向治疗的临床效果 治疗受到不可避免出现的获得性耐药性的限制，最终导致治疗失败 无效。了解这些耐药机制对于开发改进的治疗方法至关重要 改善患者治疗效果的策略。 在这个项目中，Hata 博士提议研究 EGFR 突变 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/肿瘤学教师 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肿瘤学培训项目，Hata博士加入Jeffrey博士实验室 2010 年，Engelman 在麻省总医院癌症研究中心工作，他在那里重点研究如何 细胞凋亡信号的变化会影响对靶向治疗的敏感性和耐药性。自从加入麻省总医院以来 2013年，Hata博士在Engelman实验室继续他的研究工作，现在对 运用从之前的工作中获得的见解来了解 EGFR 突变 NSCLC 的耐药性 克隆在治疗过程中出现并进化。 Hata 博士最近证明了耐药性的遗传机制，例如 EGFRT790M 突变 可以在药物治疗期间从幸存的耐药细胞中重新进化，这表明耐药细胞 尚不具有耐药性遗传机制的细菌可以作为后续耐药性的重要储存库。 抵抗力的演变。在这个项目中，Hata 博士提议研究获得性耐药性的演变 EGFR 突变型 NSCLC 患者使用 EGFR 抑制剂。检查来自患者的肿瘤活检标本 他将确定耐药细胞中积累的基因特征的疾病进展时间 耐药性癌症是否源自预先存在的耐药性亚克隆，或者是在治疗过程中进化而来。他会 将接受 EGFR 抑制剂治疗的患者的肿瘤细胞分析与功能研究相结合 来自这些相同患者的实验室肿瘤模型用于表征体内耐药肿瘤细胞。 最后，他将研究旨在体内靶向耐药细胞的新型药物治疗策略。这些 研究将显着增强我们对获得性耐药性在临床中如何演变的理解 确定延迟或防止耐药性出现的新治疗策略。 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、麻省总医院癌症中心和更大的达纳法伯/哈佛癌症中心社区。下 Engelman 博士的主要指导，他将与基因组学领域的专家密切合作 表观遗传学，以及 MGH 胸部肿瘤学和介入肺病学组的临床医生。 为了监督他的科学和职业发展，他成立了一个内部指导委员会 以及在基础和转化肿瘤学方面拥有丰富专业知识和良好记录的外部教师 在向独立过渡期间指导初级教师。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。 该项目将对 EGFR 抑制剂获得性耐药的演变产生新的见解。 NSCLC 以及对靶向治疗的总体耐药性，并将为未来的治疗策略提供信息 旨在延迟或预防临床中获得性耐药。此外，该项目将提供关键的 为哈塔博士确立自己作为该领域独立研究者的地位提供研究和培训支持 转化肺癌研究。 ！