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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. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-10-116590v1 112/4/1346    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Coluccia, A. M. L. Articles by Vacca, A. Search for Related Content PubMed PubMed Citation Articles by Coluccia, A. M. L. Articles by Vacca, A. Related Collections Hemostasis, Thrombosis, and Vascular Biology Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Validation of PDGFRβ and c-Src tyrosine kinases as tumor/vessel targets in patients with multiple myeloma: preclinical efficacy of the novel, orally available inhibitor dasatinib Addolorata Maria Luce Coluccia1,2, Teresa Cirulli1, Paola Neri3, Domenica Mangieri4, Maria Cristina Colanardi1, Antonio Gnoni1, Nicola Di Renzo5, Franco Dammacco1, Pierfrancesco Tassone3, Domenico Ribatti4, Carlo Gambacorti-Passerini2, and Angelo Vacca1 1 Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari; 2 Department of Clinical Medicine, University of Milano-Bicocca, Milan; 3 University of Magna Græcia and Cancer Center, Campus Germaneto, Catanzaro; 4 Department of Human Anatomy and Histology, University of Bari Medical School, Bari; and 5 Unit of Hematology, Hospital Vito Fazzi, Lecce, Italy Inhibition of multiple myeloma (MM) plasma cells in their permissive bone marrow microenvironment represents an attractive strategy for blocking the tumor/vessel growth associated with the disease progression. However, target specificity is an essential aim of this approach. Here, we identified platelet-derived growth factor (PDGF)–receptor beta (PDGFRβ) 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/PDGFRβ kinase axis promoted MM tumor growth and vessel sprouting by activating ERK1/2, AKT, and the transcription of MMEC-released proangiogenic 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 antitumor/vessel activity of dasatinib, a novel orally bioactive PDGFRβ/Src TK-inhibitor that significantly delayed MM tumor growth and angiogenesis in vivo, showing a synergistic cytotoxicity with conventional and novel antimyeloma drugs (ie, melphalan, prednisone, bor-tezomib, and thalidomide). Overall data highlight the biologic and therapeutic relevance of the combined targeting of PDGFRβ/c-Src TKs in MM, providing a framework for future clinical trials. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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