TY - JOUR
T1 - The small-molecule VEGF receptor inhibitor pazopanib (GW786034B) targets both tumor and endothelial cells in multiple myeloma
AU - Podar, Klaus
AU - Tonon, Giovanni
AU - Sattler, Martin
AU - Tai, Yu-Tzu
AU - Legouill, Steven
AU - Yasui, Hiroshi
AU - Ishitsuka, Kenji
AU - Kumar, Shaji
AU - Kumar, Rakesh
AU - Pandite, Lini N
AU - Hideshima, Teru
AU - Chauhan, Dharminder
AU - Anderson, Kenneth C
PY - 2006/12/19
Y1 - 2006/12/19
N2 - A critical role for vascular endothelial factor (VEGF) has been demonstrated in multiple myeloma (MM) pathogenesis. Here, we characterized the effect of the small-molecule VEGF receptor inhibitor pazopanib on MM cells in the bone marrow milieu. Pazopanib inhibits VEGF-triggered signaling pathways in both tumor and endothelial cells, thereby blocking in vitro MM cell growth, survival, and migration, and inhibits VEGF-induced up-regulation of adhesion molecules on both endothelial and tumor cells, thereby abrogating endothelial cell-MM cell binding and associated cell proliferation. We show that pazopanib is the first-in-class VEGF receptor inhibitor to inhibit in vivo tumor cell growth associated with increased MM cell apoptosis, decreased angiogenesis, and prolonged survival in a mouse xenograft model of human MM. Low-dose pazopanib demonstrates synergistic cytotoxicity with conventional (melphalan) and novel (bortezomib and immunomodulatory drugs) therapies. Finally, gene expression and signaling network analysis show transcriptional changes of several cancer-related genes, in particular c-Myc. Using siRNA, we confirm the role of c-Myc in VEGF production and secretion, as well as angiogenasis. These preclinical studies provide the rationale for clinical evaluation of pazopanib, alone and in combination with conventional and novel therapies, to increase efficacy, overcome drug resistance, reduce toxicity, and improve patient outcome in MM.
AB - A critical role for vascular endothelial factor (VEGF) has been demonstrated in multiple myeloma (MM) pathogenesis. Here, we characterized the effect of the small-molecule VEGF receptor inhibitor pazopanib on MM cells in the bone marrow milieu. Pazopanib inhibits VEGF-triggered signaling pathways in both tumor and endothelial cells, thereby blocking in vitro MM cell growth, survival, and migration, and inhibits VEGF-induced up-regulation of adhesion molecules on both endothelial and tumor cells, thereby abrogating endothelial cell-MM cell binding and associated cell proliferation. We show that pazopanib is the first-in-class VEGF receptor inhibitor to inhibit in vivo tumor cell growth associated with increased MM cell apoptosis, decreased angiogenesis, and prolonged survival in a mouse xenograft model of human MM. Low-dose pazopanib demonstrates synergistic cytotoxicity with conventional (melphalan) and novel (bortezomib and immunomodulatory drugs) therapies. Finally, gene expression and signaling network analysis show transcriptional changes of several cancer-related genes, in particular c-Myc. Using siRNA, we confirm the role of c-Myc in VEGF production and secretion, as well as angiogenasis. These preclinical studies provide the rationale for clinical evaluation of pazopanib, alone and in combination with conventional and novel therapies, to increase efficacy, overcome drug resistance, reduce toxicity, and improve patient outcome in MM.
KW - Animals
KW - Apoptosis/drug effects
KW - Blotting, Western
KW - Cell Line, Tumor
KW - Cell Movement/drug effects
KW - Endothelial Cells/drug effects
KW - Enzyme-Linked Immunosorbent Assay
KW - Gene Expression Regulation, Neoplastic/drug effects
KW - Humans
KW - Immunohistochemistry
KW - Immunoprecipitation
KW - Indazoles
KW - Mice
KW - Microarray Analysis
KW - Multiple Myeloma/drug therapy
KW - Neovascularization, Pathologic/metabolism
KW - Proto-Oncogene Proteins c-myc/genetics
KW - Pyrimidines/metabolism
KW - RNA, Small Interfering/genetics
KW - Receptors, Vascular Endothelial Growth Factor/metabolism
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Signal Transduction/drug effects
KW - Sulfonamides/metabolism
KW - Angiogenesis
KW - Xenograft mouse model
UR - http://www.scopus.com/inward/record.url?scp=33845882259&partnerID=8YFLogxK
U2 - 10.1073/pnas.0609329103
DO - 10.1073/pnas.0609329103
M3 - Journal article
C2 - 17164332
SN - 0027-8424
VL - 103
SP - 19478
EP - 19483
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 51
ER -