Junctional adhesion molecule-A is overexpressed in advanced multiple myeloma and determines response to oncolytic reovirus.

Kevin R Kelly,Erik Wendlandt,Guido Tricot,Weiguo Zhao,Fenghuang Zhan,Jennifer S Carew,Steffan T Nawrocki,Claudia M Espitia

doi:10.18632/oncotarget.5753

Abstract

Despite the development of several new agents for multiple myeloma (MM) therapy over the last decade, drug resistance continues to be a significant problem. Patients with relapsed/refractory disease have high mortality rates and desperately need new precision approaches that directly target specific molecular features that are prevalent in the refractory setting. Reolysin is a proprietary formulation of reovirus for cancer therapy that has demonstrated efficacy in multiple clinical trials. Its selective effects against solid tumors have been largely attributed to RAS-mediated control of reovirus replication. However, the mechanisms regulating its preferential anti-neoplastic effects in MM and other hematological malignancies have not been rigorously studied. Here we report that the reovirus receptor, junctional adhesion molecule-A (JAM-A) is highly expressed in primary cells from patients with MM and the majority of MM cell lines compared to normal controls. A series of experiments demonstrated that JAM-A expression, rather than RAS, was required for Reolysin-induced cell death in MM models. Notably, analysis of paired primary MM specimens revealed that JAM-A expression was significantly increased at relapse compared to diagnosis. Two different models of acquired resistance to bortezomib also displayed both higher JAM-A expression and elevated sensitivity to Reolysin compared to parental cells, suggesting that Reolysin may be an effective agent for patients with relapsed/refractory disease due to their high JAM-A levels. Taken together, these findings support further investigation of Reolysin for the treatment of patients with relapsed/refractory MM and of JAM-A as a predictive biomarker for sensitivity to Reolysin-induced cell death.

Highlights

The outcome for patients with multiple myeloma (MM), a fatal neoplasm characterized by the uncontrolled proliferation of clonal plasma cells, has improved significantly due to the development of novel treatments such as proteasome inhibitors and immunomodulatory (IMiDs) agents [1, 2]
These results were consistent with the ability of Reolysin to reduce cell viability in that all MM cell lines showed a dose-dependent diminishment of viability with the exception of OPM-2 cells, which displayed a very minimal response to Reolysin that was similar to that of normal peripheral blood mononuclear cells (PBMC) from healthy donors (Figure 1B)
We and other investigators previously demonstrated that reovirus replication triggers endoplasmic reticulum (ER) stress and apoptosis in MM cells, resulting in significant activity against MM cell lines, primary cells from patients, and in animal models of MM [12, 37]

Summary

Introduction

The outcome for patients with multiple myeloma (MM), a fatal neoplasm characterized by the uncontrolled proliferation of clonal plasma cells, has improved significantly due to the development of novel treatments such as proteasome inhibitors and immunomodulatory (IMiDs) agents [1, 2]. MM cells produce large quantities of immunoglobulins and this heavy engagement in protein synthesis results in constitutive endoplasmic reticulum (ER) stress. Combined treatment with bortezomib (BZ) and Reolysin yielded a dual accumulation of undegraded ubiquitinated proteins and viral particles resulting in the synergistic induction of ER stress and the BH3-only family member NOXA [12, 15]. These findings led to its investigation in a Phase 1 study in relapsed/refractory MM patients [16]

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Results

Conclusion