title: Enhanced efficacy of IGF1R inhibition in pediatric glioblastoma by combinatorial targeting of PDGFRα/β.
abstract: 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 have carried 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 μmol/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) α/β 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.
authors.affiliation: Paediatric Oncology, Institute of Cancer Research, Sutton, United Kingdom.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Bielen
authors.forename: Lara
authors.initials: L
authors.lastname: Perryman
authors.forename: Gary M
authors.initials: GM
authors.lastname: Box
authors.forename: Melanie
authors.initials: M
authors.lastname: Valenti
authors.forename: Alexis
authors.initials: A
authors.lastname: de Haven Brandon
authors.forename: Vanessa
authors.initials: V
authors.lastname: Martins
authors.forename: Alexa
authors.initials: A
authors.lastname: Jury
authors.forename: Sergey
authors.initials: S
authors.lastname: Popov
authors.forename: Sharon
authors.initials: S
authors.lastname: Gowan
authors.forename: Sebastien
authors.initials: S
authors.lastname: Jeay
authors.forename: Florence I
authors.initials: FI
authors.lastname: Raynaud
authors.forename: Francesco
authors.initials: F
authors.lastname: Hofmann
authors.forename: Darren
authors.initials: D
authors.lastname: Hargrave
authors.forename: Suzanne A
authors.initials: SA
authors.lastname: Eccles
authors.forename: Chris
authors.initials: C
authors.lastname: Jones
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D002648:Child; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009367:Neoplasm Staging; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C501177:NVP-AEW541; D011743:Pyrimidines; D011758:Pyrroles; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta