Translational Focus on Targeting HDAC6 with Ricolinostat Confirms Potent Activity in Preclinical Models of Lymphoma and a Favorable Toxicity Profile in Patients with Relapsed or Refractory Lymphoma

• Published in: Blood 2015-12, Vol.126 (23), p.1280-1280
• Main Authors: Amengual, Jennifer E, Renee, Lichtenstein, Rojas, Celeste, Zullo, Kelly, Lombardo, Maximilian, Lichtenstein, Emily, Neylon, Ellen, Deng, Changchun, Sawas, Ahmed, Shah, Bijal D, Wheeler, Catherine, Jones, Simon S, O'Connor, Owen A.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V126.23.1280.1280

▪ Pan-class HDAC inhibitors are active agents for select subtypes of lymphoma but are often associated with toxicities such as fatigue, diarrhea/constipation, cardiac arrhythmias and myelosuppression. HDAC6 plays a critical role in protein homeostasis by managing misfolded proteins and inducing the unfolded protein response (UPR). Ricolinostat is an isoform selective HDAC6 inhibitor. We evaluated the preclinical effects of ricolinostat and translated the findings into a multicenter Phase 1b study in patients with lymphoma (NCT 02091063). Cytotoxicity was evaluated in 16 lymphoma cell lines (8 DBCL, 4 MCL, 4 TCL) by Cell TiterGlo and Annexin V. Ricolinostat has activity with IC50 values ranging from 0.9-4.7 uM range, which is in the range observed in clinical PK studies. Ricolinostat displayed marked synergy with bortezomib, PI3K inhibitors, disatinib, alisertib, and ibrutinib with synergy coeficients of 0.24, 0.29, 0.64, 0.07, 0.16 respectively (values