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

项目总结 陈惠子，医学博士，肿瘤学研究员，医学科学家培训计划的最后一年 (80%的研究，20%的临床)在俄亥俄州立大学综合癌症中心。陈博士的职业目标 是成为一名独立而多产的内科科学家，他的研究将专注于 结合快速研究探讨晚期实体瘤耐药机制 尸检和基因组学。作为职业发展和走向独立的进一步培训的载体，Dr。 陈的K08建议侧重于基因组学在复发患者尸检快速研究中的应用 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，由 Sameek Roychowdhury，医学博士(主要导师，基因组学和分子诊断学专业知识)；David Carbone，医学博士，博士(共同导师，肺癌和治疗学专业知识)；Lang Li，博士(共同导师， 生物信息学方面的专业知识)。她进一步制定了职业发展计划，目标明确为(1) 精通领导力和项目管理，(2)发展分析和项目管理方面的专业知识 基因组数据的解释，以及(3)获得持续的评估和反馈。这些目标将是 通过与导师的定期和有组织的会议、正式的教学和参加研讨会来实现 和区域/国家会议。复发性小细胞肺癌是一种影响患者的无情和侵袭性的癌症。 在全球范围内，尽管铂类药物的初始应答率为60%-70%，但对几乎没有什么疗法有反应 化疗。小细胞肺癌复发的研究一直受到复发时肿瘤样本稀缺的限制。 由于病人在临床上迅速死亡。为了解决这一未得到满足的需求，陈博士发起了一项新的研究 俄亥俄州立大学对晚期癌症患者的尸检研究是全国仅有的十个项目之一。的主要目标是 陈博士的K08建议是描述小细胞肺癌化疗耐药的基因组改变。穿过 她将完成一项结合了研究尸检、基因组学和生物信息学的多学科方法 40例多发性转移瘤标本和血浆循环肿瘤DNA的全外显子组测序 小细胞肺癌合并化疗难治性疾病。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， 证明了小细胞肺癌具有早期克隆多样性的遗传异质性。最后，陈医生展示了 CtDNA突变与多发性转移肿瘤之间的高度一致性，显示了 小细胞肺癌患者ctDNA的检测陈博士希望通过分析一大群(n=40) 小细胞肺癌患者。作为一名独立的内科科学家，识别关键的基因组变化是她的长期目标 调解化疗耐药，设计“液体活检”检测小细胞肺癌患者中是否出现耐药，以及 开发针对这些变化的治疗方法。

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.