PROJECT SUMMARY/ABSTRACT: Michael Binkley, MD, MS is an Assistant Professor of Radiation Oncology at Stanford University School of Medicine. His long-term career goal is to combine his expertise in managing patients with hematologic malignancies with his research expertise in statistics, genomics, and cancer biology to develop improved treatment approaches for patients. He aims to develop a translational research program analyzing human tumor and blood samples to identify genomic and microenvironmental factors predictive of clinical outcomes to optimize therapy. This career development award will provide Dr. Binkley with the necessary training, support, and mentorship to develop his research program and gain independence. The proposal will be completed under the primary mentorship of Maximilian Diehn, MD, PhD, and Ash Alizadeh, MD, PhD who are both experts in identifying genomic biomarkers and clinically meaningful microenvironmental factors. The career development plan includes formal coursework, seminars, conferences, and hands-on approaches to allow Dr. Binkley to acquire critical knowledge and expertise in (1) cancer biology and immunology, (2) biostatistics, data management, and predictive modeling, and (3) design of prospective clinical protocols and grantsmanship. Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare subtype of Hodgkin lymphoma that is most commonly treated with intensive chemotherapy with or without radiotherapy. The majority of patients have excellent outcomes but their survival can be threatened by secondary toxicities including cardiotoxicities. To reduce therapy associated morbidity and mortality through de-escalation of therapy by identifying low risk patients and those at high risk of cardiotoxicity, this proposal seeks to (1) describe cell state ecosystems predictive of outcome, (2) use circulating tumor DNA to genotype NLPHL and establish its utility as a surveillance tool for those with advanced stage disease, and (3) establish noninvasive testing of inherited coronary artery disease risk. This proposal will lay the foundation for future prospective clinical trials employing microenvironmental factors to select patients suitable for therapy de-escalation.

PROJECT NARRATIVE The majority of patients with nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) receive treatment with intensive chemotherapy with or without radiotherapy yet are at very low risk of lymphoma-specific death and are subsequently at risk for potentially fatal cardiotoxicity. We propose to identify cell state ecosystems predictive of clinical outcome, establish novel methods to genotype NLPHL, and quantify inherited risk of cardiovascular disease with the goal to inform a risk-adapted approach to management. This project will fuel the development of prospective clinical trials evaluating rational selection of patients suitable for de-escalation of therapy to optimize treatment for NLPHL and reduce therapy associated deaths.