TY - JOUR
T1 - Histone deacetylase inhibitors enhance the therapeutic potential of reovirus in multiple myeloma
AU - Stiff, Andrew
AU - Caserta, Enrico
AU - Sborov, Douglas W.
AU - Nuovo, Gerard J.
AU - Mo, Xiaokui
AU - Schlotter, Sarah Y.
AU - Canella, Alessandro
AU - Smith, Emily
AU - Badway, Joseph
AU - Old, Matthew
AU - Jaime-Ramirez, Alena Cristina
AU - Yan, Pearlly
AU - Benson, Don M.
AU - Byrd, John C.
AU - Baiocchi, Robert
AU - Kaur, Balveen
AU - Hofmeister, Craig C.
AU - Pichiorri, Flavia
N1 - Funding Information:
A. Stiff was supported by The Ohio State University Pelotonia research fellowship and D.W. Sborov was supported under Award Number T32CA165998. C.C. Hofmeister and F. Pichiorri were supported by NIH R21CA156222. This research was also supported by grants from the Multiple Myeloma Opportunities for Research & Education (MMORE) and NIH R21CA156222 (to C.C. Hofmeister).
Publisher Copyright:
© 2016 American Association for Cancer Research.
PY - 2016/5
Y1 - 2016/5
N2 - 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.
AB - 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.
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U2 - 10.1158/1535-7163.MCT-15-0240-T
DO - 10.1158/1535-7163.MCT-15-0240-T
M3 - Article
C2 - 26809490
AN - SCOPUS:84969581239
SN - 1535-7163
VL - 15
SP - 830
EP - 841
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 5
ER -