Histone deacetylase inhibitors enhance the therapeutic potential of reovirus in multiple myeloma

Andrew Stiff, Enrico Caserta, Douglas W. Sborov, Gerard J. Nuovo, Xiaokui Mo, Sarah Y. Schlotter, Alessandro Canella, Emily Smith, Joseph Badway, Matthew Old, Alena Cristina Jaime-Ramirez, Pearlly Yan, Don M. Benson, John C. Byrd, Robert Baiocchi, Balveen Kaur, Craig C. Hofmeister, Flavia Pichiorri

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)830-841
Number of pages12
JournalMolecular cancer therapeutics
Volume15
Issue number5
DOIs
StatePublished - May 2016
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Histone deacetylase inhibitors enhance the therapeutic potential of reovirus in multiple myeloma'. Together they form a unique fingerprint.

Cite this