Genomic characterization of tumor heterogeneity in recurrent small cell lung cancer through research autopsy

项目摘要 Hui-Zi Chen，MD，PhD，是一名内科肿瘤学研究员，正在参加医师科学家培训计划的最后一年 (80%的研究，20%的诊所）在俄亥俄州州立大学综合癌症中心。陈博士的职业目标 是成为一个独立的和富有成效的医生科学家，其研究将集中在确定 结合快速研究探讨晚期恶性实体瘤的耐药机制 尸检和基因组学作为职业发展和进一步独立培训的工具，博士。 Chen的K 08提案侧重于基因组学在复发性乳腺癌患者快速研究尸检中的应用。 小细胞肺癌（SCLC）。为了帮助她的研究，她组建了一个指导委员会， Sameek Roychowdhury，MD，PhD（主要导师，基因组学和分子诊断专业知识）;大卫 Carbone，MD，PhD（共同导师，肺癌和治疗学方面的专业知识）; Lang Li，PhD（共同导师， 生物信息学专业）。她进一步制定了职业发展计划，目标明确：（1） 熟练掌握领导能力和项目管理，（2）发展分析方面的专业知识， 基因组数据的解释，和（3）获得持续的评估和反馈。这些目标将 通过与导师定期举行有组织的会议、正式教学和参加讲习班来实现 区域/国家会议。复发性SCLC是一种影响患者的无情和侵袭性癌症 全球范围内，尽管对铂类药物的初始应答率为60-70%， 化疗复发性小细胞肺癌的研究一直受到复发时肿瘤样本稀缺的限制 因为病人在临床上很快死亡。为了解决这一未满足的需求，陈博士开展了一项新的研究， 在俄勒冈州立大学进行的晚期癌症患者尸检研究，是全国仅有的十个项目之一。的主要目标 博士Chen的K 08建议是表征SCLC中化学抗性的基因组改变。通过 一个多学科的方法相结合的研究尸检，基因组学和生物信息学，她将完成 多个转移性肿瘤样品的全外显子组测序（WES）和40例患者的血浆循环肿瘤DNA 化疗难治性疾病的SCLC患者。到目前为止，陈博士已经证明了她的项目的可行性 因为她已经监督了五名患者的尸检，外显子组测序和生物信息学分析， 复发性小细胞肺癌这些尸检能够评估转移性肿瘤的克隆性， 表明小细胞肺癌是遗传异质性与早期克隆多样化。最后，陈博士展示了 ctDNA突变与多发性转移性肿瘤之间的高度一致性，显示了 SCLC患者的ctDNA。陈博士希望通过分析一个大的队列（n=40）来扩展这些发现。 SCLC患者作为一名独立的医生科学家，她的长期目标是确定关键的基因组改变， 介导化疗耐药性，设计“液体活检”测定以检测它们在SCLC患者中的出现，以及 开发针对这些改变的疗法。

PROJECT SUMMARY Hui-Zi Chen, MD, PhD, is a Medical Oncology fellow in her final year of the Physician Scientist Training Program (80% research, 20% clinic) at The Ohio State University Comprehensive Cancer Center. Dr. Chen's career goal is to become an independent and productive physician scientist whose research will focus on identifying mechanisms of therapeutic resistance in advanced solid tumor malignancies through combining rapid research autopsy and genomics. As a vehicle for career development and further training towards independence, Dr. Chen's K08 proposal focuses on the application of genomics for rapid research autopsy of patients with recurrent small cell lung cancer (SCLC). To assist her research, she assembled a mentoring committee consisting of Sameek Roychowdhury, MD, PhD (primary mentor, expertise in genomics and molecular diagnostics); David Carbone, MD, PhD (co-mentor, expertise in lung cancer and therapeutics); and Lang Li, PhD (co-mentor, expertise in bioinformatics). She has further devised a career development plan with clear objectives of (1) gaining proficiency in leadership and project management, (2) developing expertise in the analysis and interpretation of genomic data, and (3) obtaining continuous evaluation and feedback. These objectives will be achieved through regular and structured meetings with mentors, formal didactics, and attendance of workshops and regional/national conferences. Recurrent SCLC is a relentless and aggressive cancer affecting patients globally that responds to few, if any, therapies, despite an initial response rate of 60-70% to platinum-based chemotherapy. The study of recurrent SCLC has been limited by scarce tumor samples at time of recurrence due to the rapid clinical demise of patients. To solve this unmet need, Dr. Chen has launched a new research autopsy study for advanced cancer patients at OSU, one of just ten programs nationally. The main objective of Dr. Chen's K08 proposal is to characterize genomic alterations underlying chemoresistance in SCLC. Through a multi-disciplinary approach combining research autopsy, genomics, and bioinformatics, she will complete whole exome sequencing (WES) of multiple metastatic tumor samples and plasma circulating tumor DNA of forty SCLC patients with chemorefractory disease. Thus far, Dr. Chen has demonstrated the feasibility of her project as she has already supervised the autopsy, exome sequencing and bioinformatics analysis of five patients with recurrent SCLC. These autopsies enable the assessment of clonality in metastatic tumors and have demonstrated that SCLC is genetically heterogeneous with early clonal diversification. Finally, Dr. Chen showed high level of concordance between mutations in ctDNA and multiple metastatic tumors, showcasing the utility of ctDNA in SCLC patients. Dr. Chen hopes to expand on these findings by analyzing a large cohort (n=40) of SCLC patients. It is her long-term goal as an independent physician scientist to identify key genomic alterations mediating chemoresistance, devise `liquid biopsy' assays to detect their emergence in SCLC patients, and develop therapies targeting these alterations.