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Blood, 1 February 2006, Vol. 107, No. 3, pp. 1092-1100.
Prepublished online as a Blood First Edition Paper on October 18, 2005; DOI 10.1182/blood-2005-03-1158.


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Submitted March 23, 2005
Accepted July 27, 2005

Anti-myeloma activity of heat shock protein-90 inhibition

Constantine S Mitsiades*, Nicholas S Mitsiades, Ciaran J McMullan, Vassiliki Poulaki, Andrew L Kung, Faith E Davies, Gareth Morgan, Masaharu Akiyama, Reshma Shringarpure, Nikhil C Munshi, Paul G Richardson, Teru Hideshima, Dharminder Chauhan, Xuesong Gu, Charles Bailey, Marie Joseph, Towia A Libermann, Neal S Rosen, and Kenneth C Anderson

Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA
Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA
Departments of Cell Biology and Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
Royal Marsden Hospital and Institute of Cancer Research, Sutton, Surrey, United Kingdom
BIDMC Genomics Center, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, Boston, MA, USA
Memorial Sloan-Kettering Cancer Center, New York, NY, USA

* Corresponding author; email: Constantine_Mitsiades{at}dfci.harvard.edu.

We show that multiple myeloma (MM), the 2nd most commonly diagnosed hematologic malignancy, is responsive to hsp90 inhibitors in vitro and in clinically-relevant orthotopic in vivo models, even though this disease does not depend on HER2/neu, bcr/abl, androgen or estrogen receptors or other hsp90 chaperoning clients which are hallmarks of tumor types traditionally viewed as attractive clinical settings for use of hsp90 inhibitors. This class of agents simultaneously suppress in MM cells the expression and/or function multiple levels of insulin-like growth factor receptor (IGF-1R) and interleukin-6 receptor (IL-6R) signaling (e.g. IKK/NF-{kappa}B, PI-3K/Akt, and Raf/MAPK); and downstream effectors (e.g. proteasome, telomerase and HIF-1{alpha} activities). These pleiotropic pro-apoptotic effects allow hsp90 inhibitors to abrogate paracrine, bone marrow stromal cell-derived, protection on MM tumor cells, and sensitize them to other anti-cancer agents, including cytotoxic chemotherapy and proteasome inhibitors. These results indicate that hsp90 can be targeted therapeutically in neoplasias that may not express or depend on molecules previously considered to be the main hsp90 client proteins. This not only suggests a more general role for hsp90 in chaperoning tumor- or tissue type-specific constellations of client proteins with critical involvement in proliferative and anti-apoptotic cellular responses and paves the way for more extensive future therapeutic applications of hsp90 inhibition in diverse neoplasias, including MM.


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