Northeastern University


Biochemistry, '24

Characterizing Resistance to Immunogenic Cell Death in the Treatment Multiple Myeloma with Bortezomib

Mentor: Kenneth C. Anderson, M.D.

Institution: Dana Farber Cancer Institute

Multiple myeloma (MM) is the second most common hematological malignancy; it’s a malignancy of plasma cells, which are terminally differentiated B lymphocytes that are primarily proliferating in the bone marrow. MM is always preceded by two precursor asymptomatic conditions, called monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Clinical manifestations of multiple myeloma are the result of aberrant monoclonal protein production, and include hypercalcemia, renal failure, anemia, and bone disease with lytic lesions. One of the most promising fields of treatment for multiple myeloma is immunotherapy. Indeed, immunomodulatory drugs and proteasome inhibitors (PIs) have shown both great clinical success and promise. Bortezomib, a proteasome inhibitor, is currently one of the most effective agents in treatment of multiple myeloma, as malignant plasma cells are dependent on the function of the proteasome due to the high protein turnover. Importantly, bortezomib has been recently described not only as a cytotoxic agent but also as an immunogenic drug. Indeed, the Anderson lab has recently shown that bortezomib triggers immunogenic cell death (ICD), a process by which tumor cell proteins are recognized as a damage-associated molecular pattern (DAMP), which in turn triggers a specific immune response to the cancer cells. The Anderson lab has been working on characterizing the ICD response associated with bortezomib. My research project will be focused on identifying tumor mechanisms of ICD resistance. One of the key targets for the project is GABARAP, a protein identified as crucial for immune recognition of MM tumor cells and specifically lost in high-risk MM patients with deletion of the chromosome arm 17p. We hope to identify the mechanisms underlying ICD resistance and to find new therapeutic approaches to restore ICD sensitivity in MM patients, specifically those carrying high-risk chromosomal abnormalities.