Smac mimetics and innate immune stimuli synergize to promote tumor death.
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.
Solange Gauthier Karsh Molecular Genetics Laboratory, Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.
Shawn T
ST
Beug
Solange Gauthier Karsh Molecular Genetics Laboratory, Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.
Vera A
VA
Tang
Solange Gauthier Karsh Molecular Genetics Laboratory, Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.
Eric C
EC
LaCasse
Solange Gauthier Karsh Molecular Genetics Laboratory, Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.
Herman H
HH
Cheung
Solange Gauthier Karsh Molecular Genetics Laboratory, Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.
Caroline E
CE
Beauregard
Solange Gauthier Karsh Molecular Genetics Laboratory, Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.
Jan
J
Brun
Solange Gauthier Karsh Molecular Genetics Laboratory, Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.
Jeffrey P
JP
Nuyens
Solange Gauthier Karsh Molecular Genetics Laboratory, Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.
Nathalie
N
Earl
Solange Gauthier Karsh Molecular Genetics Laboratory, Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.
Martine
M
St-Jean
Solange Gauthier Karsh Molecular Genetics Laboratory, Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.
Janelle
J
Holbrook
Alberta Children's Hospital Research Institute, Department of Microbiology, Immunology and Infectious Disease, University of Calgary, Calgary, Alberta, Canada.
Himika
H
Dastidar
Alberta Children's Hospital Research Institute, Department of Microbiology, Immunology and Infectious Disease, University of Calgary, Calgary, Alberta, Canada.
Douglas J
DJ
Mahoney
Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
Carolina
C
Ilkow
Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
Fabrice
F
Le Boeuf
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.
John C
JC
Bell
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.
Robert G
RG
Korneluk
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D051017:Apoptosis Regulatory Proteins / Q000494:pharmacology* / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects*; D016207:Cytokines / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D057809:HEK293 Cells; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology / Q000627:therapeutic use; D050130:Oncolytic Virotherapy; D011070:Poly I-C / Q000494:pharmacology / Q000627:therapeutic use
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; D009838:Oligodeoxyribonucleotides; D011070:Poly I-C