title: Sirtuin and pan-class I/II deacetylase (DAC) inhibition is synergistic in preclinical models and clinical studies of lymphoma.
abstract: Understanding the molecular pathogenesis of lymphoma has led to paradigm-changing treatment opportunities. One example involves tailoring specific agents based on the cell of origin in aggressive lymphomas. Germinal center (GC)-derived diffuse large B-cell lymphoma (DLBCL) is known to be driven by an addiction to Bcl6, whereas the activated B-cell (ABC) subtype is driven by nuclear factor κB. In the GC subtype, there is a critical inverse relationship between Bcl6 and p53, the functional status of which is linked to each transcription factor's degree of acetylation. Deacetylation of Bcl6 is required for its transcriptional repressor effects allowing for the oncogene to drive lymphomagenesis. Conversely, acetylation of p53 is activating when class III deacetylases (DACs), or sirtuins, are inhibited by niacinamide. Treatment of DLBCL cell lines with pan-DAC inhibitors in combination with niacinamide produces synergistic cytotoxicity in GC over ABC subtypes. This correlated with acetylation of both Bcl6 and p53. This combination also produced remissions in a spontaneous aggressive B-cell lymphoma mouse model expressing Bcl6. In a phase 1 proof-of-principle clinical trial, 24% of patients with relapsed or refractory lymphoma attained a response to vorinostat and niacinamide, and 57% experienced disease stabilization. We report herein on the preclinical and clinical activity of this targeted strategy in aggressive lymphomas. This trial was registered at www.clinicaltrials.gov as #NCT00691210.
authors.affiliation: Center for Lymphoid Malignancies, Columbia University, New York, NY;
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Amengual
authors.forename: Sean
authors.initials: S
authors.lastname: Clark-Garvey
authors.forename: Matko
authors.initials: M
authors.lastname: Kalac
authors.forename: Luigi
authors.initials: L
authors.lastname: Scotto
authors.forename: Enrica
authors.initials: E
authors.lastname: Marchi
authors.forename: Ellen
authors.initials: E
authors.lastname: Neylon
authors.forename: Paul
authors.initials: P
authors.lastname: Johannet
authors.forename: Ying
authors.initials: Y
authors.lastname: Wei
authors.forename: Jasmine
authors.initials: J
authors.lastname: Zain
authors.forename: Owen A
authors.initials: OA
authors.lastname: O'Connor
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000328:Adult; D000368:Aged; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D009536:Niacinamide / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D037761:Sirtuins / Q000378:metabolism*; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C411984:BCOR protein, human; D056572:Histone Deacetylase Inhibitors; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D009536:Niacinamide; D037761:Sirtuins; D006655:Histone Deacetylases