Lymphoma is a term for cancers that start in the cells of lymph system. Though lymphomas account for 5% of all cancers globally, they are a significant concern in the spectrum of hematologic diseases. Lymphomas are associated with multiple types and subtypes with distinct molecular signatures, diagnosis and treatment challenging. While genomic and transcriptomic studies over the last decade have advanced our understanding of disease initiation and progression, key questions related to regulatory mechanisms and treatment response remain unresolved. Proteomics plays a crucial role in understanding disease characteristics, as alterations in protein expression, modification, and interaction are fundamental to the development and progression of diseases. However, technical challenges associated with proteomics and limited access to well-characterized sample cohorts have restricted the large-scale application of proteomics in lymphoma research. To address this complexity, at the Precision Proteomics Center, we have established a highly sensitive, robust, semi-automated, mass spectrometry platform enabling large-scale proteomics of clinical material. With this platform, we aim to advance disease characterization and treatment response prediction to drive precision medicine in lymphoma.
Lymphoma samples are obtained through the University Hospital Zurich biobank, comprising over 2,000 clinically annotated cases across diverse lymphoma types. Baseline proteomic profiling of untreated patient material is performed on both lymphoma tissues and primary cells. To study both effectiveness of drugs and its underlying mechanism of action, ex vivo drug perturbation experiments are conducted in blood-derived primary lymphoma cells across multiple drugs, concentrations and time points.
Our first lymphoma cohort focused on rare and aggressive mantle cell lymphoma (MCL) and served as a proof-of-concept for large-scale lymphoma proteomics. In both tissue samples and primary cells, we identified proteins associated with disease-related biological features, such as markers relevant for subtype classification, providing a basis for future diagnostic applications. To further understand how these proteomic landscapes change upon treatment, we systematically evaluate effects of protein inhibitors and degraders across multiple lymphoma types. So far, we have characterized treatment responses to selected therapeutic agents in primary samples of Chronic Lymphocytic Leukemia (CLL), and Marginal Zone Lymphoma (MZL). We specifically studied the effect of a novel targeted protein degrader (NX-5948) across the lymphomas, observing consistent target engagement and dose-dependent proteomic response. Comparison with a clinically established inhibitor targeting the same protein (ibrutinib) revealed both shared and degrader-specific proteomic signatures, highlighting mechanistic differences between inhibition and targeted degradation. Further comparison of our ex vivo perturbation data with in vivo inhibitor treatment response demonstrated strong downstream effect similarity, highlighting the platform's capacity to resolve drug-specific molecular mechanisms in a clinically relevant setting.