Characterization of an imatinib-sensitive subset of high-grade human glioma cultures.

High-grade gliomas,including glioblastomas,are malig-nant brain tumors for which improved treatment isurgently needed. Genetic studies have demonstrated theexistence of biologically distinct subsets. Preliminarystudies have indicated that platelet-derived growth factor(PDGF) receptor signaling contributes to the growth ofsome of these tumors. In this study,human high-gradeglioma primary cultures were analysed for sensitivity totreatment with the PDGF receptor inhibitor imatinib/Glivec/Gleevec/STI571. Six out of 15 cultures displayedmore than 40% growth inhibition after imatinib treat-ment,whereas seven cultures showed less than 20%growth inhibition. In the sensitive cultures,apoptosiscontributed to growth inhibition. Platelet-derived growthfactor receptor status correlated with imatinib sensitivity.Supervised analyses of gene expression profiles andreal-time PCR analyses identified expression of thechemokine CXCL12/SDF-1 (stromal cell-derived factor1) as a predictor of imatinib sensitivity. Exogenousaddition of CXCL12 to imatinib-insensitive culturesconferred some imatinib sensitivity. Finally,coregulationof CXCL12 and PDGF a-receptor was observed inglioblastoma biopsies. We have thus defined the char-acteristics of a novel imatinib-sensitive subset of gliomacultures,and provided evidence for a functional relation-ship between imatinib sensitivity and chemokine signaling.These findings will assist in the design and evaluation ofclinical trials exploring therapeutic effects of imatinib onmalignant brain tumors.Oncogene(2006)25, 4913–4922.doi:10.1038/sj.onc.1209497;published online 20 March 2006Keywords: PDGF receptor; imatinib; CXCL12;glioblastoma multiforme; microarrayIntroductionHigh-grade gliomas are the most common malignantbrain tumor of the adult. Treatment is presently basedon a combination of surgery, radiation therapy andchemotherapy. However, with these treatment moda-lities, responses are extremely poor. A recent popula-tion-based analysis of glioblastoma reported 17.7% 1-year survival and 3.3% 2-year survival (Ohgaki et al.,2004). Identification of novel treatment strategies istherefore highly warranted.Glioblastoma has been broadly divided into primaryand secondary glioblastomas (Kleihues et al., 2002).Secondary glioblastomas progress from lower gradegliomas, and also occur more frequently in youngerpatients,whereasprimaryglioblastomasappeardenovo.Primary glioblastomas are characterized by ampli-fication of an often mutated epidermal growth factor(EGFR) gene, whereas secondary glioblastomas areassociated with p53 mutations and overexpression ofPlatelet derived growth factor (PDGF) and PDGFreceptors. Recent studies have identified a novel subsetamong the secondary glioblastomas characterized byoverexpression of genes on chromosome 12q13–14(Mischel etal., 2003). Expression profiling and geneticanalysesofhigh-gradegliomashavealsoidentifiednovelpredictors of prognosis (Backlund et al., 2003; Nuttetal., 2003; Freije etal., 2004; Liang etal., 2005).PDGF and PDGF receptors are commonly coex-pressedinhigh-gradegliomas,suggestingthatautocrinePDGF receptor stimulation may contribute to theirgrowth (Hermanson et al., 1992; Westermark et al.,1995). This notion has experimental support. Glioma-liketumorscanbeinducedinmiceafteroverproductionof PDGF in mouse brain (Uhrbom et al., 1998; Daietal., 2001). Also, some glioma-derived cell lines havebeen blocked by interference with PDGF receptorsignaling (Shamah et al., 1993; Strawn et al., 1994;Kilic etal., 2000).TheinterestinPDGFreceptorsascancerdrugtargetshas increased with the availability of clinically usefulPDGFantagonistslikeimatinib/Glivec/Gleevec/STI571(Pietras et al., 2003). Imatinib is an orally availabletyrosine kinase inhibitor, which, in addition to PDGFreceptors, also inhibits c-Kit, c-Abl, Bcr-Abl and Arg