5159

PDGFRB

CD140B|JTK12|PDGFR|PDGFR-1|PDGFR1;platelet-derived growth factor receptor, beta polypeptide;PDGFRB;platelet-derived growth factor receptor, beta polypeptide

CD140 antigen-like family member B|PDGF-R-beta|PDGFR-beta|beta-type platelet-derived growth factor receptor|platelet-derived growth factor receptor 1|platelet-derived growth factor receptor beta

5q33.1

protein-coding

PURPOSE: We previously showed that overexpression of epidermal growth factor receptor (EGFR) is associated with malignant grade in childhood glioma. The objective of this study was to determine whether protein expression of EGFR or platelet-derived growth factor receptor (PDGFR) and their active signaling pathways are related to malignant histology, progression of disease, and worse survival. EXPERIMENTAL DESIGN: Tissue microarrays were prepared from untreated tumors from 85 new glioma patients [22 high-grade gliomas (HGG) and 63 low-gradegliomas (LGG)] diagnosed at this institution from 1989 to 2004. Immunohistochemistry was used to assess total expression of EGFR, PDGFR beta, and PTEN and expression of phosphorylated EGFR, phosphorylated PDGFR alpha (p-PDGFR alpha), phosphorylated AKT, phosphorylated mitogen-activated protein kinase, andphosphorylated mammalian target of rapamycin. These results were correlated withclinicopathologic data, including extent of initial tumor resection, evidence ofdissemination, tumor grade, proliferation index, and survival, as well as with Affymetrix gene expression profiles previously obtained from a subset of these tumors. RESULTS: High expression of p-PDGFR alpha, EGFR, PDGFR beta, and phosphorylated EGFR was seen in 85.7%, 80.0%, 78.9%, and 47.4% of HGG and 40.0%,87.1%, 41.7%, and 30.6% of LGG, respectively. However, high expression of p-PDGFR alpha and PDGFR beta was the only significant association with malignant histology (P = 0.031 and 0.005, respectively); only the loss of PTEN expression was associated with worse overall survival. None of these targets, either alone or in combination, was significantly associated with progression-free survival in either LGG or HGG. CONCLUSIONS: High PDGFR protein expression is significantly associated with malignant histology in pediatric gliomas, but it does not represent an independent prognostic factor. Deficient PTEN expression is associated with worse overall survival in HGG.

pediatric glioblastoma (pGBM), although rare, is one of the leading causes of cancer-related deaths in children, with tumors essentially refractory to existing treatments. We have identified IGF1R to be a potential therapeutic target in pGBM due to gene amplification and high levels of IGF2 expression in some tumor samples, as well as constitutive receptor activation in pGBM cell lines. To evaluate the therapeutic potential of strategies targeting the receptor, we havecarried out in vitro and in vivo preclinical studies using the specific IGF1R inhibitor NVP-AEW541. A modest inhibitory effect was seen in vitro, with GI(50) values of 5 to 6 mumol/L, and concurrent inhibition of receptor phosphorylation.Specific targeting of IGF1R with short interfering RNA decreased cell viability,diminished downstream signaling through phosphoinositide 3-kinase (PI3K), and induced G(1) arrest, effects mimicked by NVP-AEW541, both in the absence and presence of IGF2. Hallmarks of PI3K inhibition were observed after treatment with NVP-AEW541 by expression profiling and Western blot analysis. Phospho-receptor tyrosine kinase (RTK) arrays showed phosphorylation of platelet-derived growth factor receptor (PDGFR) alpha/beta in pGBM cells, suggesting coactivation of an alternative RTK pathway. Treatment of KNS42 with the PDGFR inhibitor imatinib showed additional effects targeting the mitogen-activated protein kinase pathway, and cotreatment of the PDGFR inhibitor imatinib with NVP-AEW541 resulted in a highly synergistic interaction in vitro and increased efficacy after 14 days therapy in vivo compared with either agent alone. These data provide evidence that inhibition of IGF1R, in combination with other targeted agents, may be a useful and novel therapeutic strategy in pGBM.#CI- (c)2011 AACR