Platelet‐derived growth factor receptor as a prognostic marker and a therapeutic target for imatinib mesylate therapy in osteosarcoma

• Published in: Cancer 2008-05, Vol.112 (10), p.2119-2129
• Main Authors: Kubo, Tadahiko, Piperdi, Sajida, Rosenblum, Jeremy, Antonescu, Cristina R., Chen, Wen, Kim, Han‐Soo, Huvos, Andrew G., Sowers, Rebecca, Meyers, Paul A., Healey, John H., Gorlick, Richard
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Benzamides; Biological and medical sciences; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Blotting, Western; Bone Neoplasms - drug therapy; Bone Neoplasms - metabolism; Bone Neoplasms - secondary; Cell Survival - drug effects; Child; Diseases of the osteoarticular system; Female; Gleevec; Humans; Imatinib Mesylate; Immunoenzyme Techniques; Immunoprecipitation; Male; Medical sciences; Middle Aged; Mitogen-Activated Protein Kinases - metabolism; osteosarcoma; Osteosarcoma - drug therapy; Osteosarcoma - metabolism; Osteosarcoma - pathology; Phosphorylation; Piperazines - therapeutic use; Platelet-Derived Growth Factor - metabolism; platelet‐derived growth factor receptor (PDGF); Prognosis; Protein Kinase Inhibitors - therapeutic use; Protein-Tyrosine Kinases - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-sis; Pyrimidines - therapeutic use; Receptor, Platelet-Derived Growth Factor alpha - genetics; Receptor, Platelet-Derived Growth Factor alpha - metabolism; Receptor, Platelet-Derived Growth Factor beta - genetics; Receptor, Platelet-Derived Growth Factor beta - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; STI‐571; Tumor Cells, Cultured; Tumors; Tumors of striated muscle and skeleton
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/cncr.23437

The purpose of this review was to determine whether imatinib mesylate (STI571, Gleevec) has a role in the treatment of osteosarcoma. The expression of platelet‐derived growth factor (PDGF) receptor and its ligand was examined in a panel of surgical specimens obtained from 54 osteosarcoma patients, and then the expression was compared with prognosis. The effects of imatinib mesylate on growth and molecular events in 10 patient‐derived osteosarcoma cell cultures were investigated. Immunohistochemical studies demonstrated frequent expression of PDGF‐AA (80.4%) and PDGF‐α receptor (79.6%) and their correlation with inferior event‐free survival (P < .05). PDGF‐B–B and PDGF‐β–receptor expressions were also frequent (75.4% and 86%, respectively); however, statistically significant inferior event‐free survival was not demonstrated (P = .15). In vitro studies demonstrated that imatinib mesylate had a variable cytotoxic effect on various osteosarcoma primary cultures, with an IC50 of 5.6 μM to 9.5 μM, and blocked the PDGF‐induced intracellular signal transduction as well as inhibition of downstream Akt phosphorylation. Mitogen‐activated protein kinase (MAPK) was constitutively activated despite PDGF stimulation and imatinib mesylate treatment in 7 of 10 osteosarcoma cultures, perhaps explaining uncontrolled proliferation and relative unresponsiveness to imatinib. Imatinib mesylate could not be viewed as having a role as a single agent at current conventional doses for the treatment of osteosarcoma. These findings predicted activity in osteosarcoma clinical trials and suggested that in vitro model systems predict clinical behavior and that PDGF and its receptor expression could potentially be used for determining prognosis of osteosarcoma. Cancer 2008. ©2008 American Cancer Society. To determine the role of imatinib mesylate (STI571, Gleevec) in the treatment of osteosarcoma, the expression of platelet‐derived growth factor (PDGF) receptor and its ligand was examined in osteosarcoma patient specimens and related to prognosis. The effects of imatinib mesylate on growth and molecular events in osteosarcoma primary cultures were investigated. Immunohistochemical studies demonstrated frequent expression of PDGF receptor and its ligand and their correlation with inferior event‐free survival (P < .05). In vitro studies demonstrated that imatinib mesylate had a variable cytotoxic effect on various osteosarcoma primary cultures and blocked the PDGF‐induced intracellular sign