|
|
Blood, 15 May 2008, Vol. 111, No. 10, pp. 5068-5077.
Prepublished online as a Blood First Edition Paper on March 11, 2008; DOI 10.1182/blood-2007-09-115170.
 Previous Article | Table of Contents | Next Article 
NEOPLASIA
Targeting NF- B in Waldenstrom macroglobulinemia
Xavier Leleu1,2,*,
Jérôme Eeckhoute1,*,
Xiaoying Jia1,
Aldo M. Roccaro1,
Anne-Sophie Moreau1,2,
Mena Farag1,
Antonio Sacco1,
Hai T. Ngo1,
Judith Runnels1,
Molly R. Melhem1,
Nicolas Burwick1,
Abdelkareem Azab1,
Feda Azab1,
Zachary Hunter1,
Evdoxia Hatjiharissi1,
Daniel R. Carrasco1,
Steven P. Treon1,
Thomas E. Witzig3,
Teru Hideshima1,
Myles Brown1,
Kenneth C. Anderson1, and
Irene M. Ghobrial1
1 Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA;
2 Service des Maladies du Sang et Laboratoire d'Immunologie, CHRU, Lille, France; and
3 Division of Hematology, Mayo Clinic, Rochester, MN
The nuclear factor- B (NF-B) path-way has been implicated in tumor B-cell survival, growth, and resistance to therapy. Because tumor cells overcome single-agent antitumor activity, we hypothesized that combination of agents that target differentially NF-B pathway will induce significant cytotoxicity. Therapeutic agents that target proteasome and Akt pathways should induce significant activity in B-cell malignancies as both pathways impact NF-B activity. We demonstrated that perifosine and bortezomib both targeted NF-B through its recruitment to the promoter of its target gene IB using chromatin immunoprecipitation assay. This combination led to synergistic cytotoxicity in Waldenstrom macroglobulinemia (WM) cells that was mediated through a combined reduction of the PI3K/Akt and ERK signaling pathways, found to be critical for survival of WM cells. Moreover, a combination of these drugs with the CD20 monoclonal antibody rituximab further increased their cytotoxic activity. Thus, effective WM therapy may require combination regimens targeting the NF-B pathway.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
| |
