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Nat Biotechnol. 2014 Feb;32(2):182-90. doi: 10.1038/nbt.2806. Epub 2014 Jan 26.

Smac mimetics and innate immune stimuli synergize to promote tumor death.

Author information

1
Solange Gauthier Karsh Molecular Genetics Laboratory, Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.
2
Alberta Children's Hospital Research Institute, Department of Microbiology, Immunology and Infectious Disease, University of Calgary, Calgary, Alberta, Canada.
3
Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
4
1] Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. [2] Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
5
1] Solange Gauthier Karsh Molecular Genetics Laboratory, Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada. [2] Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.

Abstract

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-β), tumor necrosis factor alpha (TNF-α) 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.

PMID:
24463573
PMCID:
PMC5030098
DOI:
10.1038/nbt.2806
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

RGK is a scientific founder and shareholder of Aegera Therapeutics (Pharmascience Inc., Montreal, Canada) which has a SMC under clinical development. JCB is the Chief Scientific Officer and a shareholder of Jennerex (Ottawa, Canada and San Francisco, USA), which has a Vaccinia-based oncolytic virus under clinical development.

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