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

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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.