TAK1- and IAP-inhibitors as novel approaches to multiple myeloma therapy

Abstract

TAK1- and IAP-inhibitors as novel approaches to multiple myeloma therapy Multiple myeloma is a hematological malignancy characterized by accumulation of malignant plasma cells in the bone marrow. This can lead to uncontrolled growth of myeloma cells causing bone lesions, anemia, kidney injury, and hypercalcemia. Multiple myeloma is diagnosed in more than 500 000 people each year, with median age at diagnosis approximately 70 years. Despite development of several novel therapeutic strategies, multiple myeloma remains an incurable disease. The purpose of this project was to investigate whether IAP- and TAK1-inhibitors could represent novel treatment strategies in multiple myeloma. Both IAP and TAK1 are proteins involved in regulation of cell death. Inhibitors of these proteins have been studied as therapeutic options in several types of cancer, including multiple myeloma. IAP-inhibitors have undergone clinical studies in multiple myeloma, while TAK1-inhibitors have seen limited investigations. This thesis includes experiments with multiple myeloma cell lines, patient samples and a mouse model to further elucidate the therapeutic potential of IAP- and TAK1-inhibitors in multiple myeloma. In addition, this thesis has investigated the effect of IAP- and TAK1-inhibitors on osteoclasts, the cells that cause bone destruction in myeloma bone disease. The first part of this thesis investigated the effect of TAK1-inhibitors in MM cell lines, osteoclasts, and patient samples. We found that TAK1-inhibitors induced cell death in myeloma cell lines and patient samples, both alone and in combination with chemotherapeutics such as melphalan. In addition, TAK1-inhibitors caused cell death in human osteoclasts. The second part of this thesis aimed to study the effect of TAK1-inhibitors in a multiple myeloma mouse model. We found that they had some effect on survival, but no effect on disease burden. The third part of this thesis studied the effect of IAP-inhibitors in myeloma cell lines and osteoclasts. We showed that IAP-inhibitors induce cell death in human osteoclasts but had no effect on myeloma cell lines alone. Taken together, both IAP- and TAK1-inhbitors are interesting candidates as novel treatment strategies in multiple myeloma.