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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.
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Submitted September 27, 2007
Accepted March 6, 2008
Targeting NF- B in Waldenstrom macroglobulinemia
Xavier Leleu, Jerome Eeckhoute, Xiaoying Jia, Aldo M Roccaro, Anne-Sophie Moreau, Mena Farag, Antonio Sacco, Hai T Ngo, Judith Runnels, Molly R Melham, Nicolas Burwick, Abdelkareem Azab, Feda Azab, Zachary Hunter, Evdoxia Hatjiharissi, Daniel R Carrasco, Steven P Treon, Thomas E Witzig, Teru Hideshima, Myles Brown, Kenneth C Anderson, and Irene M Ghobrial*
Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA, United States
Service des Maladies du Sang et Laboratoire d'Immunologie, CHRU, Lille, France
Division of Hematology, Mayo Clinic, Rochester, MN, United States
* Corresponding author; email: irene_ghobrial{at}dfci.harvard.edu.
The NF- B pathway 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-kB through its recruitment to the promoter of its target gene IkB using chromatin immunoprecipitation (ChIP) 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, 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.
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