PROJECT SUMMARY/ABSTRACT PIs: Ash Alizadeh, M.D./Ph.D. & Maximilian Diehn, M.D./Ph.D. Classical Hodgkin lymphoma (HL) is among the most curable human malignancies. However, strategies to personalize HL therapies and to minimize long-term attendant toxicities of chemotherapy are currently limited to baseline risk factors and imaging. This is due to our incomplete understanding of targetable pathways and lack of good biomarkers. Because of the low fraction of malignant cells in tumor tissue and consecutive technical challenges, the landscape of HL is not well-defined. Our long-term goal is to study the ability of baseline and dynamic risk factors, including genetic mutations, circulating tumor DNA (ctDNA) and imaging studies (PET), to accurately predict treatment outcomes in HL patients, and to provide a basis for individualized precision medicine. Our central hypothesis is that clinical and biological heterogeneity in HL reflects distinct genomic features that are noninvasively measurable using ultrasensitive ctDNA techniques, and that refining early response assessment integrating interim PET and blood based methods improves prognostication. We will test our hypotheses via three specific aims: (1) To noninvasively define the genomic landscape of somatic variations in HL, and to determine the relationship of genomic variants with biological heterogeneity at initial disease presentation, (2) To associate molecular features at baseline and molecular response with ultimate therapeutic outcome, and to integrate clinical and molecular biomarkers in a personalized dynamic risk model for predicting HL outcomes, and (3) To functionally characterize novel mutations in Interleukin-4 receptor (IL4R) resulting in gain-of-function IL4/STAT6 signaling, and to test the utility of precision therapeutic targeting of these mutations. If successful, our project will lead to novel ways to select better therapies for patients at highest risk of failure, and to minimize toxicity for the majority of patients responding well to standard therapy. Our innovative approach, in which we will combine blood-based methods for genotyping and disease monitoring with imaging studies, will provide the basis for a personalized treatment approach in HL.