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1.
Mol Ther ; 31(11): 3176-3192, 2023 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-37766429

RESUMO

The clinical efficacy of VSVΔ51 oncolytic virotherapy has been limited by tumor resistance to viral infection, so strategies to transiently repress antiviral defenses are warranted. Pevonedistat is a first-in-class NEDD8-activating enzyme (NAE) inhibitor currently being tested in clinical trials for its antitumor potential. In this study, we demonstrate that pevonedistat sensitizes human and murine cancer cells to increase oncolytic VSVΔ51 infection, increase tumor cell death, and improve therapeutic outcomes in resistant syngeneic murine cancer models. Increased VSVΔ51 infectivity was also observed in clinical human tumor samples. We further identify the mechanism of this effect to operate via blockade of the type 1 interferon (IFN-1) response through neddylation-dependent interferon-stimulated growth factor 3 (ISGF3) repression and neddylation-independent inhibition of NF-κB nuclear translocation. Together, our results identify a role for neddylation in regulating the innate immune response and demonstrate that pevonedistat can improve the therapeutic outcomes of strategies using oncolytic virotherapy.


Assuntos
Inibidores Enzimáticos , Proteína NEDD8 , Neoplasias , Terapia Viral Oncolítica , Animais , Humanos , Camundongos , Linhagem Celular Tumoral , Inibidores Enzimáticos/farmacologia , Interferons , Proteína NEDD8/antagonistas & inibidores , Proteína NEDD8/genética , Neoplasias/tratamento farmacológico
2.
Front Immunol ; 14: 1099459, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36969187

RESUMO

Introduction: Adipocytes in the tumour microenvironment are highly dynamic cells that have an established role in tumour progression, but their impact on anti-cancer therapy resistance is becoming increasingly difficult to overlook. Methods: We investigated the role of adipose tissue and adipocytes in response to oncolytic virus (OV) therapy in adipose-rich tumours such as breast and ovarian neoplasms. Results: We show that secreted products in adipocyte-conditioned medium significantly impairs productive virus infection and OV-driven cell death. This effect was not due to the direct neutralization of virions or inhibition of OV entry into host cells. Instead, further investigation of adipocyte secreted factors demonstrated that adipocyte-mediated OV resistance is primarily a lipid-driven phenomenon. When lipid moieties are depleted from the adipocyte-conditioned medium, cancer cells are re-sensitized to OV-mediated destruction. We further demonstrated that blocking fatty acid uptake by cancer cells, in a combinatorial strategy with virotherapy, has clinical translational potential to overcome adipocyte-mediated OV resistance. Discussion: Our findings indicate that while adipocyte secreted factors can impede OV infection, the impairment of OV treatment efficacy can be overcome by modulating lipid flux in the tumour milieu.


Assuntos
Terapia Viral Oncolítica , Vírus Oncolíticos , Neoplasias Ovarianas , Humanos , Feminino , Microambiente Tumoral , Meios de Cultivo Condicionados , Vírus Oncolíticos/fisiologia , Neoplasias Ovarianas/terapia , Lipídeos
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