Histone Deacetylase Inhibitors Enhance the Therapeutic Potential of Reovirus in Multiple Myeloma

Abstract

Multiple myeloma (MM) 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 MM confirmed tolerability, but no objective responses were evident, likely because the virus selectively entered the MM 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 MM remain unknown. Here we report that Junctional Adhesion Molecule 1 (JAM-1), the cellular receptor for RV, is epigenetically regulated in MM cells. Treatment of MM 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. Further, our data indicate that the combination of Reolysin with HDACi, potentiates RV killing activity of MM 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 MM.

Reolysin and Histone Deacetylase Inhibition in the Treatment of Head and Neck Squamous Cell Carcinoma

“…Understanding how the mechanisms of each therapeutic, or the combination thereof, can affect tumors and the anti-tumor immune response is critical to enhancing patient outcomes. Recent reports show that HDAC inhibition in myeloma cells results in the upregulation of the Reolysin entry receptor, JAM-1, thus allowing for greater Reolysin infection and killing both in vitro and in vivo 8 . Consistent with these findings, we observed JAM-1 expression and sensitivity to Reolysin killing in HNSCC tumor cells following treatment with the HDAC inhibitors AR-42 or SAHA.…”

“…WB using anti-σ-NS (reovirus capsid protein) and anti-JAM-1 (reovirus entry receptor) antibodies was performed as previously described 8 . WB results were quantified using ImageJ software (NIH).…”

“…Similar to Reolysin, SAHA is also being investigated for safety and efficacy in patients with head and neck cancer and preliminary results are promising 7 . HDAC inhibition in myeloma cells has recently been reported to upregulate the Reolysin entry receptor, junctional adhesion molecule 1 (JAM-1), and allows for greater Reolysin infection and killing both in vitro and in vivo in myeloma-bearing nude mice 8 . Importantly, the prevalence of JAM-1 in various cancer types has yet to be thoroughly explored.…”

Development of oncolytic virotherapy: from genetic modification to combination therapy

“…Reolysin ® has received an orphan drug designation from the US FDA and EMA for the treatment of gastric and pancreatic cancers [31]. In the treatment of multiple myeloma, the single use of Reolysin® did not show obvious antitumor activity [66]. However, when Reoly-sin® was combined with chemotherapy, such as carboplatin and paclitaxel, it exhibited improved therapeutic efficacy with an objective response rate (ORR) of up to 21% in the treatment of malignant melanoma [19].…”

Development of oncolytic virotherapy for the treatment of oral cancer – At the waiting stage for clinical use

“…Several HDAC inhibitors have been shown to exhibit antitumor activities in many cancers by arresting the growth of and/or inducing apoptosis in cancer cells [165,166]. Moreover, HDAC inhibitors augment the viral replication and antitumor efficacy of oncolytic viruses including vaccinia virus, HSV-1, VSV, adenoviruses, and reoviruses [167][168][169][170][171][172]. Enhanced oncolytic activity has been correlated with the dampening of cellular IFN responses and augmentation of virus-induced cell death [167,173].…”