title: Enhancement of pomalidomide anti-tumor response with ACY-241, a selective HDAC6 inhibitor.
abstract: Thalidomide-based Immunomodulatory Drugs (IMiDs®), including lenalidomide and pomalidomide, are effective therapeutics for multiple myeloma. These agents have been approved with, or are under clinical development with, other targeted therapies including proteasome inhibitors, αCD38 monoclonal antibodies, as well as histone deacetylase (HDAC) inhibitors for combination therapy. HDAC inhibitors broadly targeting Class I and IIb HDACs have shown potent preclinical efficacy but have frequently demonstrated an undesirable safety profile in combination therapy approaches in clinical studies. Therefore, development of more selective HDAC inhibitors could provide enhanced efficacy with reduced side effects in combination with IMiDs® for the treatment of B-cell malignancies, including multiple myeloma. Here, the second generation selective HDAC6 inhibitor citarinostat (ACY-241), with a more favorable safety profile than non-selective pan-HDAC inhibitors, is shown to synergize with pomalidomide in in vitro assays through promoting greater apoptosis and cell cycle arrest. Furthermore, utilizing a multiple myeloma in vivo murine xenograft model, combination treatment with pomalidomide and ACY-241 leads to increased tumor growth inhibition. At the molecular level, combination treatment with ACY-241 and pomalidomide leads to greater suppression of the pro-survival factors survivin, Myc, and IRF4. The results presented here demonstrate synergy between pomalidomide and ACY-241 in both in vitro and in vivo preclinical models, providing further impetus for clinical development of ACY-241 for use in combination with IMiDs for patients with multiple myeloma and potentially other B-cell malignancies.
authors.affiliation: Acetylon Pharmaceuticals, Boston, Massachusetts, United States of America.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: North
authors.affiliation: Acetylon Pharmaceuticals, Boston, Massachusetts, United States of America.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Almeciga-Pinto
authors.affiliation: Acetylon Pharmaceuticals, Boston, Massachusetts, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Tamang
authors.affiliation: Acetylon Pharmaceuticals, Boston, Massachusetts, United States of America.
authors.forename: Min
authors.initials: M
authors.lastname: Yang
authors.affiliation: Acetylon Pharmaceuticals, Boston, Massachusetts, United States of America.
authors.forename: Simon S
authors.initials: SS
authors.lastname: Jones
authors.affiliation: Acetylon Pharmaceuticals, Boston, Massachusetts, United States of America.
authors.forename: Steven N
authors.initials: SN
authors.lastname: Quayle
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D051379:Mice; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D013792:Thalidomide; C467566:pomalidomide; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases