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Blood, 1 May 2004, Vol. 103, No. 9, pp. 3474-3479.
Prepublished online as a Blood First Edition Paper on November 26, 2003; DOI 10.1182/blood-2003-10-3527.
Submitted October 14, 2003
Accepted November 21, 2003
The pan-inhibitor of VEGF receptors GW654652 blocks growth and migration of multiple myeloma cells in the bone marrow microenvironment
Klaus Podar, Laurence P Catley, Yu-Tzu Tai, Reshma Shringarpure, Pedro Carvalho, Toshiaki Hayashi, Renate Burger, Robert L Schlossman, Paul G Richardson, Lini N Pandite, Rakesh Kumar, Teru Hideshima, Dharminder Chauhan, and Kenneth C Anderson*
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
Department of Pediatric Hematology and Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
GlaxoSmithKline, Research Triangle Park, NC, USA
* Corresponding author; email: kenneth_anderson{at}dfci.harvard.edu.
Prior studies have shown that multiple myeloma (MM) cell line and MM patient cells express high-affinity vascular-endothelial-growth-factor (VEGF) receptor-1 or Flt-1, but not VEGF receptor-2 or Flk-1/ KDR, and that VEGF triggers MM cell proliferation via a MAPK-dependent pathway and migration via a PKC-dependent pathway. The present study evaluates the efficacy of the small molecule tyrosine-kinase inhibitor GW654652, which inhibits all three VEGF receptors with similar potency. We show that GW654652 acts both directly on MM cells and in the bone marrow microenvironment. Specifically, GW654652 (1-10µg/mL) inhibits VEGF-triggered migrational activity and MM cell proliferation of MM cell lines that are sensitive and resistant to conventional therapy in a dose-dependent fashion. As expected from our previous studies of VEGF-induced signaling and sequelae in MM cells, GW654652 blocked both VEGF-induced Flt-1-phosphorylation and downstream activation of AKT-1 and MAPK-signaling cascades. Importantly, GW654652 also inhibits interleukin-6- and VEGF-secretion and proliferation of MM cells induced by tumor cell-binding to BM stromal cells. The activity of a pan-VEGFR inhibitor against MM cells in the BM milieu, coupled with its lack of major toxicity in preclinical mouse models, provides the framework for clinical trials of this drug-class to improve patient outcome in MM.
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