title: The combination of hypomethylating agents and histone deacetylase inhibitors produce marked synergy in preclinical models of T-cell lymphoma.
abstract: T-cell lymphomas (TCL) are aggressive lymphomas usually treated with CHOP (cyclophsophamide, doxorubicin, vincristine, prednisolone)-like regimens upfront. Recent data suggest that TCL are driven by epigenetic defects, potentially rendering them sensitive to epigenetic therapies. We explored the therapeutic merits of a combined epigenetic platform using histone deacetylase inhibitors (HDACIs) and DNA methyltransferase inhibitors (DNMT) in in vitro and in vivo models of TCL. The 50% inhibitory concentration (IC50) values revealed romidepsin was the most potent HDACI, with an IC50in the low nanomolar range. The combination with a hypomethylating agent produced synergy across all cell lines, which was confirmed in cytotoxicity and apoptosis assays. An in vivo xenograft study demonstrated inhibition of tumour growth in the combination cohort compared to the single agent. Gene expression array and global methylation profiling revealed differentially expressed genes and modulated pathways for each of the single treatment conditions and the combination. Most of the effects induced by the single agent treatment were maintained in the combination group. In total, 944 unique genes were modulated by the combination treatment, supporting the hypothesis of molecular synergism. These data suggest combinations of hypomethylating agents and HDACIs are synergistic in models of TCL, which is supported at the molecular level.
authors.affiliation: Department of Medicine, Center for Lymphoid Malignancies, Columbia University Medical Center, New York, NY, USA.
authors.forename: Enrica
authors.initials: E
authors.lastname: Marchi
authors.affiliation: Department of Medicine, Center for Lymphoid Malignancies, Columbia University Medical Center, New York, NY, USA.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Zullo
authors.affiliation: Department of Medicine, Center for Lymphoid Malignancies, Columbia University Medical Center, New York, NY, USA.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Amengual
authors.affiliation: Department of Medicine, Center for Lymphoid Malignancies, Columbia University Medical Center, New York, NY, USA.
authors.forename: Matko
authors.initials: M
authors.lastname: Kalac
authors.affiliation: Department of Medicine, Center for Lymphoid Malignancies, Columbia University Medical Center, New York, NY, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: Bongero
authors.affiliation: Department of Medicine, Center for Lymphoid Malignancies, Columbia University Medical Center, New York, NY, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: McIntosh
authors.affiliation: Department of Pathology, NYU School of Medicine, New York, NY, USA.
authors.forename: Laura K
authors.initials: LK
authors.lastname: Fogli
authors.affiliation: Department of Hematology and Oncological Sciences "L. and A. Seràgnoli", S. Orsola Malpighi Hospital, Unit of Hematopathology, University of Bologna, Bologna, Italy.
authors.forename: Maura
authors.initials: M
authors.lastname: Rossi
authors.affiliation: Department of Hematology and Oncological Sciences "L. and A. Seràgnoli", S. Orsola Malpighi Hospital, Unit of Hematopathology, University of Bologna, Bologna, Italy.
authors.forename: Pier L
authors.initials: PL
authors.lastname: Zinzani
authors.affiliation: Department of Hematology and Oncological Sciences "L. and A. Seràgnoli", S. Orsola Malpighi Hospital, Unit of Hematopathology, University of Bologna, Bologna, Italy.
authors.forename: Stefano A
authors.initials: SA
authors.lastname: Pileri
authors.affiliation: Department of Hematology and Oncological Sciences "L. and A. Seràgnoli", S. Orsola Malpighi Hospital, Unit of Hematopathology, University of Bologna, Bologna, Italy.
authors.forename: Pier P
authors.initials: PP
authors.lastname: Piccaluga
authors.affiliation: Department of Hematology and Oncological Sciences "L. and A. Seràgnoli", S. Orsola Malpighi Hospital, Unit of Hematopathology, University of Bologna, Bologna, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Fuligni
authors.affiliation: Department of Medicine, Center for Lymphoid Malignancies, Columbia University Medical Center, New York, NY, USA.
authors.forename: Luigi
authors.initials: L
authors.lastname: Scotto
authors.affiliation: Department of Medicine, Center for Lymphoid Malignancies, Columbia University Medical Center, New York, NY, USA.
authors.forename: Owen A
authors.initials: OA
authors.lastname: O'Connor
keywords: HDAC inhibitors; T-Cell Lymphoma; epigenetic therapy; hypomethylating agents; preclinical models