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

  1. Author:
    Lee, S.
    Yagita, H.
    Sayers, T. J.
    Celis, E.

  2. Author Address

    [Lee, Sujin; Celis, Esteban] H Lee Moffitt Canc Ctr & Res Inst, Dept Immunol, Tampa, FL 33612 USA. [Yagita, Hideo] Juntendo Univ, Sch Med, Dept Immunol, Bunkyo Ku, Tokyo 1138421, Japan. [Sayers, Thomas J.] NCI Frederick, SAIC Frederick Inc, Expt Immunol Lab, Canc Inflammat Program,Ctr Canc Res, Frederick, MD 21702 USA.;Lee, S, Emory Univ, Sch Med, Dept Pediat, Childrens Healthcare Atlanta, 2015 Uppergate Dr NE,Room 510, Atlanta, GA 30322 USA.;sujin.lee@emory.edu
    1. Year: 2010
    2. Date: Jul
  2. Journal: Cancer Immunology Immunotherapy
    1. 59
    2. 7
    3. Pages: 1073-1081
  4. Type of Article: Article
  5. ISSN: 0340-7004
  1. 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 (alpha-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 alpha-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 alpha-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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External Sources

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  2. DOI: 10.1007/s00262-010-0834-0
  3. View record in Web of Science®
  4. WOS: 000277136700010

Library Notes

  1. Fiscal Year: FY2009-2010
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