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Carfilzomib is the recently approved second generation proteasome inhibitor for multiple myeloma therapy. Carfilzomib has superior clinical activity than the first generation drug, bortezomib, putatively due to less off-target activity and an altered proteasome subunit-selectivity compared with bortezomib, but consistently shows high incidence of cardiotoxicity in 5-12% of patients, which is not well understood. Cardiomyocytes, like multiple myeloma cells, rely on accurately tuned homeostasis between protein synthesis and degradation. The inhibition of proteasome activity results in excessive proteotoxic stress, which induces apoptosis in these cells. Using our well-established and unique chemical-biology tools for the analysis of human proteasome biology in living cells we shall use the start-up research funding to initiate a research line in our laboratory that aims to better understand proteolysis in human cardiomyocytes, the consequences of proteasome inhibition, and in particular the potential reasons for the unique cardiotoxicity of carfilzomib in clinical treatment.