Augmented efficacy with the combination of blockade of the NOTCH-1 pathway, Bortezomib and Romidepsin in a murine MT-1 adult T cell leukemia model

Adult T-cell leukemia (ATL) is an aggressive malignancy caused by human T-cell lymphotropic virus I (HTLV-1). There is no accepted curative therapy for ATL. We have reported that certain ATL patients have increased Notch-1 signaling along with constitutive activation of the NF-κB pathway. Physical and functional interaction between these two pathways provides the rationale to combine the γ-secretase inhibitor Compound E with the proteasome inhibitor Bortezomib. Moreover, Romidepsin, a histone deacetylase inhibitor, has demonstrated major antitumor action in leukemia/lymphoma. In this study, we investigated the therapeutic efficacy of the single agents and combinations of these agents in a murine model of human ATL, the MT-1 model. Single and double agents inhibited tumor growth as monitored by tumor size (P < .05), and prolonged survival of leukemia-bearing mice (P < .05) compared with the control group. The combination of three agents significantly enhanced the antitumor efficacy as assessed by tumor size, tumor markers in the serum (human sIL-2Rα and β(2)M), and survival of the MT-1 tumor bearing mice, compared with all other treatment groups (P < .05). Improved therapeutic efficacy obtained by combining Compound E, Bortezomib and Romidepsin supports a clinical trial of this combination in the treatment of ATL.