A12
Understanding and breaking proteasome inhibitor resistance in multiple myeloma patients
Project Summary
Proteasome inhibitors are backbone agents for multiple therapies in MM. However, virtually all patients eventually relapse. While some respond to second or third generation PIs, others do not. The underlying molecular mechanisms for this heterogeneous therapeutic response are poorly or not at all understood. While acquisition of point mutations during PI treatment is a common phenomenon in-vitro, large-scale MM genome sequencing projects have only found recurrent mutations in a limited subset of patients, suggesting additional PI resistance mechanisms in human disease. We hypothesize that major new fundamental insights will be obtained from (longitudinal) monitoring of epigenomic and proteomic changes of MM patients undergoing PI treatment. The vision of this subproject is to obtain a detailed mechanistic understanding of PI mechanism of action as well as resistance and to exploit these insights clinically by re-sensitizing relapsed MM patients to proteasome inhibitors.
