Platelet-derived growth factor receptor as a prognostic marker and a therapeutic target for imatinib mesylate therapy in osteosarcoma.
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-alpha receptor (79.6%) and their correlation with inferior event-free survival (P < .05). PDGF-B-B and PDGF-beta-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 IC(50) of 5.6 microM to 9.5 microM, 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.
Kubo
Tadahiko
T
Orthopedic Surgery Service, Memorial Sloan-Kettering Cancer Center, Weil Medical College of Cornell University, New York, New York, USA.
Piperdi
Sajida
S
Rosenblum
Jeremy
J
Antonescu
Cristina R
CR
Chen
Wen
W
Kim
Han-Soo
HS
Huvos
Andrew G
AG
Sowers
Rebecca
R
Meyers
Paul A
PA
Healey
John H
JH
Gorlick
Richard
R
D000293:Adolescent; D000328:Adult; D000368:Aged; D000077214:Becaplermin; D001549:Benzamides; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D002470:Cell Survival / Q000187:drug effects; D002648:Child; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D012516:Osteosarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D010879:Piperazines / Q000627:therapeutic use*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D001549:Benzamides; D014408:Biomarkers, Tumor; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines; D012333:RNA, Messenger; C075278:platelet-derived growth factor A; D000077214:Becaplermin; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases