Synergy of BCL2 and histone deacetylase inhibition against leukemic cells from cutaneous T-cell lymphoma patients
- PMID: 28972015
- PMCID: PMC5680613
- DOI: 10.1182/blood-2017-06-792150
Synergy of BCL2 and histone deacetylase inhibition against leukemic cells from cutaneous T-cell lymphoma patients
Abstract
The presence and degree of peripheral blood involvement in patients with cutaneous T-cell lymphoma (CTCL) portend a worse clinical outcome. Available systemic therapies for CTCL may variably decrease tumor burden and improve quality of life, but offer limited effects on survival; thus, novel approaches to the treatment of advanced stages of this non-Hodgkin lymphoma are clearly warranted. Mutational analyses of CTCL patient peripheral blood malignant cell samples suggested the antiapoptotic mediator B-cell lymphoma 2 (BCL2) as a potential therapeutic target. To test this, we developed a screening assay for evaluating the sensitivity of CTCL cells to targeted molecular agents, and compared a novel BCL2 inhibitor, venetoclax, alone and in combination with a histone deacetylase (HDAC) inhibitor, vorinostat or romidepsin. Peripheral blood CTCL malignant cells were isolated from 25 patients and exposed ex vivo to the 3 drugs alone and in combination, and comparisons were made to 4 CTCL cell lines (Hut78, Sez4, HH, MyLa). The majority of CTCL patient samples were sensitive to venetoclax, and BCL2 expression levels were negatively correlated (r = -0.52; P =018) to 50% inhibitory concentration values. Furthermore, this anti-BCL2 effect was markedly potentiated by concurrent HDAC inhibition with 93% of samples treated with venetoclax and vorinostat and 73% of samples treated with venetoclax and romidepsin showing synergistic effects. These data strongly suggest that concurrent BCL2 and HDAC inhibition may offer synergy in the treatment of patients with advanced CTCL. By using combination therapies and correlating response to gene expression in this way, we hope to achieve more effective and personalized treatments for CTCL.
© 2017 by The American Society of Hematology.
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References
-
- Girardi M, Heald PW, Wilson LD. The pathogenesis of mycosis fungoides. N Engl J Med. 2004;350(19):1978-1988. - PubMed
-
- Arulogun SO, Prince HM, Ng J, et al. . Long-term outcomes of patients with advanced-stage cutaneous T-cell lymphoma and large cell transformation. Blood. 2008;112(8):3082-3087. - PubMed
-
- Agar NS, Wedgeworth E, Crichton S, et al. . Survival outcomes and prognostic factors in mycosis fungoides/Sézary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer staging proposal. J Clin Oncol. 2010;28(31):4730-4739. - PubMed
-
- Rozati S, Cheng PF, Widmer DS, Fujii K, Levesque MP, Dummer R. Romidepsin and azacitidine synergize in their epigenetic modulatory effects to induce apoptosis in CTCL. Clin Cancer Res. 2016;22(8):2020-2031. - PubMed
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