Smac mimetics and innate immune stimuli synergize to promote tumor death

被引：103

作者：

Beug, Shawn T. ^{[1
]}

Tang, Vera A. ^{[1
]}

LaCasse, Eric C. ^{[1
]}

Cheung, Herman H. ^{[1
]}

Beauregard, Caroline E. ^{[1
]}

Brun, Jan ^{[1
]}

Nuyens, Jeffrey P. ^{[1
]}

Earl, Nathalie ^{[1
]}

St-Jean, Martine ^{[1
]}

Holbrook, Janelle ^{[1
]}

Dastidar, Himika ^{[2
]}

Mahoney, Douglas J. ^{[2
]}

Ilkow, Carolina ^{[3
]}

Le Boeuf, Fabrice ^{[3
]}

Bell, John C. ^{[3
,4
]}

Korneluk, Robert G. ^{[1
,4
]}

机构：

[1] Eastern Ontario Res Inst, Childrens Hosp, Apoptosis Res Ctr, Solange Gauthier Karsh Mol Genet Lab, Ottawa, ON, Canada

[2] Univ Calgary, Dept Microbiol Immunol & Infect Dis, Alberta Childrens Hosp Res Inst, Calgary, AB, Canada

[3] Ottawa Hosp Res Inst, Ctr Innovat Canc Therapeut, Ottawa, ON, Canada

[4] Univ Ottawa, Dept Biochem Microbiol & Immunol, Ottawa, ON, Canada

来源：

NATURE BIOTECHNOLOGY | 2014年 / 32卷 / 02期

基金：

加拿大健康研究院;

关键词：

NF-KAPPA-B; APOPTOSIS PROTEINS; ONCOLYTIC VIRUSES; VACCINIA VIRUS; IAP ANTAGONIST; CANCER-CELL; ALPHA; RECOGNITION; INTERFERON; INHIBITORS;

D O I：

10.1038/nbt.2806

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 [微生物学]; 090105 [作物生产系统与生态工程];

摘要：

Smac mimetic compounds (SMC), a class of drugs that sensitize cells to apoptosis by counteracting the activity of inhibitor of apoptosis (IAP) proteins, have proven safe in phase 1 clinical trials in cancer patients. However, because SMCs act by enabling transduction of pro-apoptotic signals, SMC monotherapy may be efficacious only in the subset of patients whose tumors produce large quantities of death-inducing proteins such as inflammatory cytokines. Therefore, we reasoned that SMCs would synergize with agents that stimulate a potent yet safe "cytokine storm." Here we show that oncolytic viruses and adjuvants such as poly(I: C) and CpG induce bystander death of cancer cells treated with SMCs that is mediated by interferon beta (IFN-beta), tumor necrosis factor alpha (TNF-alpha) and/or TNF-related apoptosis-inducing ligand (TRAIL). This combinatorial treatment resulted in tumor regression and extended survival in two mouse models of cancer. As these and other adjuvants have been proven safe in clinical trials, it may be worthwhile to explore their clinical efficacy in combination with SMCs.

引用

页码：182 / +

页数：11

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