title: Histone Deacetylase Inhibitors Enhance the Therapeutic Potential of Reovirus in Multiple Myeloma.
abstract: Multiple myeloma remains incurable and the majority of patients die within 5 years of diagnosis. Reolysin, the infusible form of human reovirus (RV), is a novel viral oncolytic therapy associated with antitumor activity likely resulting from direct oncolysis and a virus-mediated antitumor immune response. Results from our phase I clinical trial investigating single agent Reolysin in patients with relapsed multiple myeloma confirmed tolerability, but no objective responses were evident, likely because the virus selectively entered the multiple myeloma cells but did not actively replicate. To date, the precise mechanisms underlying the RV infectious life cycle and its ability to induce oncolysis in patients with multiple myeloma remain unknown. Here, we report that junctional adhesion molecule 1 (JAM-1), the cellular receptor for RV, is epigenetically regulated in multiple myeloma cells. Treatment of multiple myeloma cells with clinically relevant histone deacetylase inhibitors (HDACi) results in increased JAM-1 expression as well as increased histone acetylation and RNA polymerase II recruitment to its promoter. Furthermore, our data indicate that the combination of Reolysin with HDACi, potentiates RV killing activity of multiple myeloma cells in vitro and in vivo This study provides the molecular basis to use these agents as therapeutic tools to increase the efficacy of RV therapy in multiple myeloma. Mol Cancer Ther; 15(5); 830-41. ©2016 AACR.
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Andrew
authors.initials: A
authors.lastname: Stiff
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Enrico
authors.initials: E
authors.lastname: Caserta
authors.affiliation: Department of Internal Medicine, Oncology/Hematology Fellowship, The Ohio State University, Columbus, Ohio.
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Sborov
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Nuovo
authors.affiliation: Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio.
authors.forename: Xiaokui
authors.initials: X
authors.lastname: Mo
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Sarah Y
authors.initials: SY
authors.lastname: Schlotter
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Canella
authors.affiliation: Biomedical Sciences Graduate Program, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Emily
authors.initials: E
authors.lastname: Smith
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Joseph
authors.initials: J
authors.lastname: Badway
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio.
authors.forename: Matthew
authors.initials: M
authors.lastname: Old
authors.affiliation: Department of Neurological Surgery, Dardinger Laboratory for Neuro-oncology and Neurosciences, The Ohio State University Wexner Medical Center, Columbus, Ohio.
authors.forename: Alena Cristina
authors.initials: AC
authors.lastname: Jaime-Ramirez
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Pearlly
authors.initials: P
authors.lastname: Yan
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio.
authors.forename: Don M
authors.initials: DM
authors.lastname: Benson
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio.
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.affiliation: Department of Neurological Surgery, Dardinger Laboratory for Neuro-oncology and Neurosciences, The Ohio State University Wexner Medical Center, Columbus, Ohio.
authors.forename: Robert
authors.initials: R
authors.lastname: Baiocchi
authors.affiliation: Department of Neurological Surgery, Dardinger Laboratory for Neuro-oncology and Neurosciences, The Ohio State University Wexner Medical Center, Columbus, Ohio.
authors.forename: Balveen
authors.initials: B
authors.lastname: Kaur
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio.
authors.forename: Craig C
authors.initials: CC
authors.lastname: Hofmeister
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio. Flavia.Pichiorri@osumc.edu.
authors.forename: Flavia
authors.initials: F
authors.lastname: Pichiorri
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D015870:Gene Expression; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000628:therapy*; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D015815:Cell Adhesion Molecules; C407243:F11R protein, human; D056572:Histone Deacetylase Inhibitors; D011956:Receptors, Cell Surface; D011991:Receptors, Virus
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