|
|
Blood, 15 August 2008, Vol. 112, No. 4, pp. 1346-1356.
Prepublished online as a Blood First Edition Paper on June 4, 2008; DOI 10.1182/blood-2007-10-116590.
 Previous Article | Next Article 
Submitted October 4, 2007
Accepted March 17, 2008
Validation of PDGFR and c-Src tyrosine kinases as tumor/vessel targets in patients with multiple myeloma: preclinical efficacy of the novel, orally available inhibitor dasatinib (BMS-354825/Sprycel®)
Addolorata Maria Luce Coluccia*, Teresa Cirulli, Paola Neri, Domenica Mangieri, Maria Cristina Colanardi, Antonio Gnoni, Nicola Di Renzo, Franco Dammacco, Pierfrancesco Tassone, Domenico Ribatti, Carlo Gambacorti-Passerini, and Angelo Vacca
Department of Internal Medicine and Clinical Oncology (DIMO), University of Bari Medical School, Bari, Italy
Cancer Center, Campus Germaneto, University of "Magna Graecia", Catanzaro, Italy
Department of Human Anatomy and Histology, University of Bari Medical School, Bari, Italy
Unit of Hematology, Hospital "Vito Fazzi", Lecce, Italy
Department of Clinical Medicine, University of Milano-Bicocca, Milan, Italy
* Corresponding author; email: malu.coluccia{at}libero.it.
Inhibition of multiple myeloma (MM) plasma cells in their permissive bone-marrow microenvironment represents an attractive strategy for blocking the tumor/vessel growth associated to the disease progression. However, target specificity is an essential aim of this approach. Here, we identified platelet-derived growth factor (PDGF)-receptor beta (PDGFR ) and pp60c-Src as shared constitutively activated tyrosine-kinases (TKs) in plasma cells and endothelial cells (ECs) isolated from MM patients (MMECs). Our cellular and molecular dissection showed that the PDGF-BB/PDGFR kinase-axis promoted MM tumor growth and vessel-sprouting by activating ERK1/2, AKT and the transcription of MMEC-released pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8). Interestingly, pp60c-Src TK-activity was selectively induced by VEGF in MM tumor and ECs, and the use of small-interfering (si)RNAs validated pp60c-Src as a key signaling-effector of VEGF-loop required for MMEC survival, migration and angiogenesis. We also assessed the anti-tumor/vessel activity of dasatinib (BMS-354825/Sprycel®), a novel orally bioactive PDGFR/Src TK-inhibitor, which significantly delayed MM tumor growth and angiogenesis in vivo, showing a synergistic cytotoxicity with conventional and novel anti-myeloma drugs (i.e. melphalan, prednisone, bortezomib and thalidomide). Overall data highlight the biological and therapeutic relevance of the combined targeting of PDGFR/c-Src TKs in MM, providing a framework for future clinical trials.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
J. A. Burger, P. Ghia, A. Rosenwald, and F. Caligaris-Cappio
The microenvironment in mature B-cell malignancies: a target for new treatment strategies
Blood,
October 15, 2009;
114(16):
3367 - 3375.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Ria, K. Todoerti, S. Berardi, A. M. L. Coluccia, A. De Luisi, M. Mattioli, D. Ronchetti, F. Morabito, A. Guarini, M. T. Petrucci, et al.
Gene Expression Profiling of Bone Marrow Endothelial Cells in Patients with Multiple Myeloma
Clin. Cancer Res.,
September 1, 2009;
15(17):
5369 - 5378.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. M. Schrage, I. H. Briaire-de Bruijn, N. F.C.C. de Miranda, J. van Oosterwijk, A. H.M. Taminiau, T. van Wezel, P. C.W. Hogendoorn, and J. V.M.G. Bovee
Kinome Profiling of Chondrosarcoma Reveals Src-Pathway Activity and Dasatinib as Option for Treatment
Cancer Res.,
August 1, 2009;
69(15):
6216 - 6222.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
