title: Dependence of Wilms tumor cells on signaling through insulin-like growth factor 1 in an orthotopic xenograft model targetable by specific receptor inhibition.
abstract: We have previously demonstrated an increased DNA copy number and expression of IGF1R to be associated with poor outcome in Wilms tumors. We have now tested whether inhibiting this receptor may be a useful therapeutic strategy by using a panel of Wilms tumor cell lines. Both genetic and pharmacological targeting resulted in inhibition of downstream signaling through PI3 and MAP kinases, G(1) cell cycle arrest, and cell death, with drug efficacy dependent on the levels of phosphorylated IGF1R. These effects were further associated with specific gene expression signatures reflecting pathway inhibition, and conferred synergistic chemosensitisation to doxorubicin and topotecan. In the in vivo setting, s.c. xenografts of WiT49 cells resembled malignant rhabdoid tumors rather than Wilms tumors. Treatment with an IGF1R inhibitor (NVP-AEW541) showed no discernable antitumor activity and no downstream pathway inactivation. By contrast, Wilms tumor cells established orthotopically within the kidney were histologically accurate and exhibited significantly elevated insulin-like growth factor-mediated signaling, and growth was significantly reduced on treatment with NVP-AEW541 in parallel with signaling pathway ablation. As a result of the paracrine effects of enhanced IGF2 expression in Wilms tumor, this disease may be acutely dependent on signaling through the IGF1 receptor, and thus treatment strategies aimed at its inhibition may be useful in the clinic. Such efficacy may be missed if only standard ectopic models are considered as a result of an imperfect recapitulation of the specific tumor microenvironment.
authors.affiliation: Department of Pediatric Oncology, Institute of Cancer Research, Sutton SM2 5NG, United Kingdom.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Bielen
authors.forename: Gary
authors.initials: G
authors.lastname: Box
authors.forename: Lara
authors.initials: L
authors.lastname: Perryman
authors.forename: Lynn
authors.initials: L
authors.lastname: Bjerke
authors.forename: Sergey
authors.initials: S
authors.lastname: Popov
authors.forename: Yann
authors.initials: Y
authors.lastname: Jamin
authors.forename: Alexa
authors.initials: A
authors.lastname: Jury
authors.forename: Melanie
authors.initials: M
authors.lastname: Valenti
authors.forename: Alexis de Haven
authors.initials: Ade H
authors.lastname: Brandon
authors.forename: Vanessa
authors.initials: V
authors.lastname: Martins
authors.forename: Vincent
authors.initials: V
authors.lastname: Romanet
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: Simon P
authors.initials: SP
authors.lastname: Robinson
authors.forename: Suzanne A
authors.initials: SA
authors.lastname: Eccles
authors.forename: Chris
authors.initials: C
authors.lastname: Jones
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D045744:Cell Line, Tumor; D004563:Electrochemistry; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000503:physiopathology*; D008279:Magnetic Resonance Imaging; D051379:Mice; D019899:Paracrine Communication / Q000502:physiology; D010766:Phosphorylation; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014183:Transplantation, Heterologous; D009396:Wilms Tumor / Q000503:physiopathology*
chemical_list: C501177:NVP-AEW541; D011743:Pyrimidines; D011758:Pyrroles; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1