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

作者：Yu P; Petrus M N; Ju W; Zhang M; Conlon K C; Nakagawa M; Maeda M; Bamford R N; Waldmann T A^*

来源：Leukemia, 2015, 29(3): 556-566.

DOI：10.1038/leu.2014.241

Adult T-cell leukemia (ATL) is an aggressive malignancy caused by human T-cell lymphotropic virus-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 nuclear factor-kappa B pathway. Physical and functional interaction between these two pathways provides the rationale to combine the gamma-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 the combination 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 < 0.05), and prolonged survival of leukemia-bearing mice (P < 0.05) 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 soluble interleukin-2 receptor-alpha and beta(2)-microglobulin) and survival of the MT-1 tumor-bearing mice, compared with all other treatment groups (P < 0.05). Improved therapeutic efficacy obtained by combining compound E, bortezomib and romidepsin supports a clinical trial of this combination in the treatment of ATL.

• 出版日期2015-3