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

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...

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Autores principales: Kelly, Kevin R., Espitia, Claudia M., Zhao, Weiguo, Wendlandt, Erik, Tricot, Guido, Zhan, Fenghuang, Carew, Jennifer S., Nawrocki, Steffan T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4747405/
https://www.ncbi.nlm.nih.gov/pubmed/26513296
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author Kelly, Kevin R.
Espitia, Claudia M.
Zhao, Weiguo
Wendlandt, Erik
Tricot, Guido
Zhan, Fenghuang
Carew, Jennifer S.
Nawrocki, Steffan T.
author_facet Kelly, Kevin R.
Espitia, Claudia M.
Zhao, Weiguo
Wendlandt, Erik
Tricot, Guido
Zhan, Fenghuang
Carew, Jennifer S.
Nawrocki, Steffan T.
author_sort Kelly, Kevin R.
collection PubMed
description 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.
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spelling pubmed-47474052016-03-24 Junctional adhesion molecule-A is overexpressed in advanced multiple myeloma and determines response to oncolytic reovirus Kelly, Kevin R. Espitia, Claudia M. Zhao, Weiguo Wendlandt, Erik Tricot, Guido Zhan, Fenghuang Carew, Jennifer S. Nawrocki, Steffan T. Oncotarget Research Paper 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. Impact Journals LLC 2015-10-15 /pmc/articles/PMC4747405/ /pubmed/26513296 Text en Copyright: © 2015 Kelly et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Kelly, Kevin R.
Espitia, Claudia M.
Zhao, Weiguo
Wendlandt, Erik
Tricot, Guido
Zhan, Fenghuang
Carew, Jennifer S.
Nawrocki, Steffan T.
Junctional adhesion molecule-A is overexpressed in advanced multiple myeloma and determines response to oncolytic reovirus
title Junctional adhesion molecule-A is overexpressed in advanced multiple myeloma and determines response to oncolytic reovirus
title_full Junctional adhesion molecule-A is overexpressed in advanced multiple myeloma and determines response to oncolytic reovirus
title_fullStr Junctional adhesion molecule-A is overexpressed in advanced multiple myeloma and determines response to oncolytic reovirus
title_full_unstemmed Junctional adhesion molecule-A is overexpressed in advanced multiple myeloma and determines response to oncolytic reovirus
title_short Junctional adhesion molecule-A is overexpressed in advanced multiple myeloma and determines response to oncolytic reovirus
title_sort junctional adhesion molecule-a is overexpressed in advanced multiple myeloma and determines response to oncolytic reovirus
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4747405/
https://www.ncbi.nlm.nih.gov/pubmed/26513296
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