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Blood, 9 July 2009, Vol. 114, No. 2, pp. 371-379. Prepublished online as a Blood First Edition Paper on May 5, 2009; DOI 10.1182/blood-2008-11-191577. This Article Full Text (PDF) All Versions of this Article: blood-2008-11-191577v1 114/2/371    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Fulciniti, M. Articles by Munshi, N. C. Search for Related Content PubMed PubMed Citation Articles by Fulciniti, M. Articles by Munshi, N. C. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted November 25, 2008 Accepted April 20, 2009 Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma Mariateresa Fulciniti, Pierfrancesco Tassone, Teru Hideshima, Sonia Vallet, Puru Nanjappa, Seth A. Ettenberg, Zhenxin Shen, Nipun Patel, Yu-tzu Tai, Dharminder Chauhan, Constantine Mitsiades, Rao Prabhala, Noopur Raje, Kenneth C. Anderson, David R. Stover, and Nikhil C. Munshi* Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA, United States University of "Magna Graecia", Catanzaro, Italy Novartis Institutes for Biomedical Research, Oncology Biotherapeutics, Cambridge, MA, United States Beth Israel Deaconess Medical Center, Boston, MA, United States VA Boston Healthcare System, Harvard Medical School, Boston, MA, United States * Corresponding author; email: nikhil_munshi{at}dfci.harvard.edu. Decreased activity of osteoblasts (OB) contributes to osteolytic lesions in multiple myeloma (MM). The production of the soluble Wnt inhibitor Dickkopf-1 (DKK1) by MM cells inhibits OB activity and its serum level correlates with focal bone lesions in MM. Therefore, we have evaluated bone anabolic effects of a DKK1 neutralizing antibody (BHQ880) in MM. In vitro BHQ880 increased OB differentiation, neutralized the negative effect of MM cells on osteoblastogenesis, and reduced IL-6 secretion. In a SCID-hu murine model of human MM, BHQ880 treatment lead to a significant increase in OB number, serum human osteocalcin level and trabecular bone. Although BHQ880 had no direct effect on MM cell growth, it significantly inhibited growth of MM cells in the presence of BM stromal cells (BMSC) in vitro. This effect was associated with inhibition of BMSC/MM cell adhesion and production of IL-6. Additionally, BHQ880 upregulated -catenin level while downregulating NF-B activity in BMSC. Interestingly, we also observed in vivo inhibition of MM cell growth by BHQ880 treatment in the SCID-hu murine model. These results confirm DKK1 as an important therapeutic target in myeloma and provide the rationale for clinical evaluation of BHQ880 to improve bone disease and to inhibit MM growth. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Fulciniti, T. Hideshima, C. Vermot-Desroches, S. Pozzi, P. Nanjappa, Z. Shen, N. Patel, E. S. Smith, W. Wang, R. Prabhala, et al. A High-Affinity Fully Human Anti-IL-6 mAb, 1339, for the Treatment of Multiple Myeloma Clin. Cancer Res., December 1, 2009; 15(23): 7144 - 7152. [Abstract] [Full Text] [PDF]

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