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Optimized combination therapy using bortezomib, TRAIL and TLR agonists in established breast tumors

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Abstract

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.

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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.

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Author notes

  1. Sujin Lee

    Present address: Department of Pediatrics, Infectious Disease, Emory University School of Medicine, Children’s Healthcare of Atlanta, 2015 Uppergate Dr NE, Room 510, Atlanta, GA, 30322, USA

Authors and Affiliations

  1. Department of Immunology, Moffitt Cancer Center, 12902 Magnolia Drive SRB-2, Tampa, FL, 33612, USA

    Sujin Lee & Esteban Celis

  2. Department of Immunology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, 113-8421, Japan

    Hideo Yagita

  3. SAIC-Frederick Inc., Laboratory for Experimental Immunology, Cancer Inflammation Program, Center for Cancer Research, NCI-Frederick, Frederick, MD, 21702, USA

    Thomas J. Sayers

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  1. Sujin Lee
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Corresponding author

Correspondence to Sujin Lee.

Electronic supplementary material

Tumor growths for individual tumor in untreated or therapy treated virgin female Balb/neuT mice at different time points are illustrated in Fig. S1. Mammary pads were inspected twice every week to monitor tumor appearance. Measurable/palpable masses >2 mm in diameter were regarded as tumors. In all cases, when mice had tumors >20 mm in the greatest dimension or when skin ulceration occurred, they were euthanized by CO2 inhalation according to our Institutional Animal Care and Use Committee guidelines.

262_2010_834_MOESM1_ESM.ppt

Figure S1. Individual tumor regression in Balb-neuT mice by combination therapy with bortezomib, α-DR5, and CpG. Control mice (N1 and N2) were left untreated. Mice (A, B, C, and D) were given bortezomib (25 μg per injection, i.v. route), -DR5 (50 μg per injection, i.v. route), and GpG (50 μg per mouse, i.t. route) as shown in Fig 5. All animals were monitored for tumor appearance by manual examination of the mammary glands every 5 days. Measurable masses > 2mm diameter were regarded as tumors (PPT 190 kb)

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Lee, S., Yagita, H., Sayers, T.J. et al. Optimized combination therapy using bortezomib, TRAIL and TLR agonists in established breast tumors. Cancer Immunol Immunother 59, 1073–1081 (2010). https://doi.org/10.1007/s00262-010-0834-0

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  • DOI: https://doi.org/10.1007/s00262-010-0834-0

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