Sirtuin and pan-class I/II deacetylase (DAC) inhibition is synergistic in preclinical models and clinical studies of lymphoma

• Published in: Blood 2013-09, Vol.122 (12), p.2104-2113
• Main Authors: Amengual, Jennifer E., Clark-Garvey, Sean, Kalac, Matko, Scotto, Luigi, Marchi, Enrica, Neylon, Ellen, Johannet, Paul, Wei, Ying, Zain, Jasmine, O'Connor, Owen A.
• Format: Article
• Language: English
• Subjects: Acetylation - drug effects; Adult; Aged; Animals; Cell Line, Tumor; Cell Survival - drug effects; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Synergism; Female; Histone Deacetylase Inhibitors - adverse effects; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylase Inhibitors - therapeutic use; Histone Deacetylases - metabolism; Humans; Inhibitory Concentration 50; Lymphoma, Large B-Cell, Diffuse - drug therapy; Lymphoma, Large B-Cell, Diffuse - metabolism; Lymphoma, Large B-Cell, Diffuse - pathology; Male; Mice; Middle Aged; Niacinamide - adverse effects; Niacinamide - pharmacology; Niacinamide - therapeutic use; Proto-Oncogene Proteins - metabolism; Repressor Proteins - metabolism; Sirtuins - metabolism; Treatment Outcome; Tumor Burden - drug effects; Tumor Suppressor Protein p53 - metabolism; Xenograft Model Antitumor Assays
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2013-02-485441

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. •Treatment of DLBCL with the combination of sirtuin and DAC inhibitors leads to synergistic cytotoxicity and acetylation of Bcl6 and p53.•The overall response rate of relapsed lymphoma patients treated with vorinostat and niacinamide was 24%, and an additional 57% achieved stable disease.