ABSTRACT
Multiple myeloma (MM) remains an incurable hematological malignancy. Combination regimens of conventional and novel drugs have improved patient's survival. However, most patients inevitably relapse and become refractory to the current therapeutic armamentarium. We investigated the efficacy of combining the microtubule-targeting agent STK405759 with dexamethasone or bortezomib in vitro and in vivo. STK405759 combined with dexamethasone or bortezomib had synergistic cytotoxic activity in RPMIS, CAG and MM1.S human MM cell lines through activation of caspase 2, 3, 8, 9 and PARP. These treatments remained cytotoxic in the presence of bone marrow stroma cells. In other MM cells, including cells resistant to vincristine, melphalan, mitoxantrone or dexamethasone, these combinations decreased significantly survival as compared to single agents. In in vivo studies, STK405759 disrupted existing blood vessels in xenograft tumors, acting not only as a cytotoxic agent but also as an anti-angiogenic drug. Mice treated with STK405759 in combination with dexamethasone or bortezomib resulted in greater tumor growth inhibition, increased overall response and prolonged survival as compared to as compared to BTZ or DEXA alone. Their anticancer activity was mediated by activation of apoptosis and reduction of tumor microvessel density. These preclinical studies provide the rationale for future clinical trials of STK405759, dexamethasone and bortezomib combinations to improve the outcome of multiple myeloma patients.
