Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada.
Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
Sci Transl Med. 2018 Jan 24;10(425). doi: 10.1126/scitranslmed.aao1613.
Resistance to oncolytic virotherapy is frequently associated with failure of tumor cells to get infected by the virus. Dimethyl fumarate (DMF), a common treatment for psoriasis and multiple sclerosis, also has anticancer properties. We show that DMF and various fumaric and maleic acid esters (FMAEs) enhance viral infection of cancer cell lines as well as human tumor biopsies with several oncolytic viruses (OVs), improving therapeutic outcomes in resistant syngeneic and xenograft tumor models. This results in durable responses, even in models otherwise refractory to OV and drug monotherapies. The ability of DMF to enhance viral spread results from its ability to inhibit type I interferon (IFN) production and response, which is associated with its blockade of nuclear translocation of the transcription factor nuclear factor κB (NF-κB). This study demonstrates that unconventional application of U.S. Food and Drug Administration-approved drugs and biological agents can result in improved anticancer therapeutic outcomes.
对溶瘤病毒治疗的抵抗常常与肿瘤细胞无法被病毒感染有关。富马酸二甲酯（DMF），一种常见的治疗银屑病和多发性硬化症的药物，也具有抗癌特性。我们发现 DMF 和各种富马酸和马来酸酯（FMAEs）可增强几种溶瘤病毒（OVs）对癌细胞系和人类肿瘤活检的感染，改善了耐药同源和异种移植肿瘤模型中的治疗效果。这导致了持久的反应，即使在对 OV 和药物单药治疗均有抗性的模型中也是如此。DMF 增强病毒传播的能力源于其抑制 I 型干扰素（IFN）产生和反应的能力，这与其阻断转录因子核因子 κB（NF-κB）的核易位有关。这项研究表明，对美国食品和药物管理局批准的药物和生物制剂的非常规应用可以带来改善的抗癌治疗效果。
