TY - JOUR
T1 - Optimized combination therapy using bortezomib, TRAIL and TLR agonists in established breast tumors
AU - Lee, Sujin
AU - Yagita, Hideo
AU - Sayers, Thomas J.
AU - Celis, Esteban
N1 - Funding Information:
Acknowledgments This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, R01CA80782 and R01CA103921 (E. Celis), under contracts NO1-CO-12400 and HSN261200800001E (T. Sayers). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. This Research was supported (in part) by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health.
PY - 2010/7
Y1 - 2010/7
N2 - TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family of cytokines, which can induce apoptosis in various tumor cells by engaging the receptors, DR4 and DR5. Bortezomib (Velcade) is a proteasome inhibitor that has been approved for patients with multiple myeloma. There is some experimental evidence in preclinical models that bortezomib can enhance the susceptibility of tumors to TRAIL-induced apoptosis. In this study, we investigated the effects of TRAIL-induced death using an agonistic antibody to the TRAIL receptor DR5 (α-DR5) in combination with bortezomib administered to mice previously injected with breast cancer cells (TUBO). This combination had some beneficial therapeutic effect, which was significantly enhanced by the co-administration of a Toll-like receptor 9 agonist (CpG). In contrast, single agent treatments had little effect on tumor growth. In addition, we evaluated the effect of combination with α-DR5, bortezomib, and CpG in the prevention/treatment of spontaneous mammary tumors in Balb-neuT mice. In this model, which is more difficult to treat, we observed dramatic antitumor effects of α-DR5, bortezomib and CpG combination therapy. Since such a mouse model more accurately reflects the immunological tolerance that exists in human cancer, our results strongly suggest that these combination strategies could be directly applied to the therapy for cancer patients.
AB - TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family of cytokines, which can induce apoptosis in various tumor cells by engaging the receptors, DR4 and DR5. Bortezomib (Velcade) is a proteasome inhibitor that has been approved for patients with multiple myeloma. There is some experimental evidence in preclinical models that bortezomib can enhance the susceptibility of tumors to TRAIL-induced apoptosis. In this study, we investigated the effects of TRAIL-induced death using an agonistic antibody to the TRAIL receptor DR5 (α-DR5) in combination with bortezomib administered to mice previously injected with breast cancer cells (TUBO). This combination had some beneficial therapeutic effect, which was significantly enhanced by the co-administration of a Toll-like receptor 9 agonist (CpG). In contrast, single agent treatments had little effect on tumor growth. In addition, we evaluated the effect of combination with α-DR5, bortezomib, and CpG in the prevention/treatment of spontaneous mammary tumors in Balb-neuT mice. In this model, which is more difficult to treat, we observed dramatic antitumor effects of α-DR5, bortezomib and CpG combination therapy. Since such a mouse model more accurately reflects the immunological tolerance that exists in human cancer, our results strongly suggest that these combination strategies could be directly applied to the therapy for cancer patients.
KW - Balb-neuT mice
KW - Bortezomib
KW - Breast tumors
KW - CpG
KW - α-DR5
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U2 - 10.1007/s00262-010-0834-0
DO - 10.1007/s00262-010-0834-0
M3 - Article
C2 - 20213120
AN - SCOPUS:77953071740
SN - 0340-7004
VL - 59
SP - 1073
EP - 1081
JO - Cancer Immunology, Immunotherapy
JF - Cancer Immunology, Immunotherapy
IS - 7
ER -