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Acute Leukemias

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

Leukemia volume 29, pages 556–566 (2015)Cite this article

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Abstract

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-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 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-α and β2-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.

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Acknowledgements

This work was supported by the Intramural Research Program of Center for Cancer Research, NCI, NIH.

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Authors and Affiliations

  1. Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

    P Yu, M N Petrus, W Ju, M Zhang, K C Conlon, M Nakagawa & T A Waldmann

  2. Laboratory Animal Science Program, SAIC-Frederick Inc., NCI-Frederick, Frederick, MD, USA

    M Zhang

  3. Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto, Japan

    M Maeda

  4. Transponics, Jacobus, PA, USA

    R N Bamford

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  1. P Yu
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Correspondence to T A Waldmann.

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Yu, P., Petrus, M., Ju, W. et al. 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. Leukemia 29, 556–566 (2015). https://doi.org/10.1038/leu.2014.241

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