A preclinical study demonstrating the efficacy of nilotinib in inhibiting the growth of pediatric high-grade glioma.
Solid tumors arising from malignant transformation of glial cells are one of the leading causes of central nervous system tumor-related death in children. Recurrence in spite of rigorous surgical and chemoradiation therapies remains a major hurdle in management of these tumors. Here, we investigate the efficacy of the second-generation receptor tyrosine kinase inhibitor nilotinib as a therapeutic option for the management of pediatric gliomas. We have utilized two independent pediatric high-grade glioma cell lines with either high platelet-derived growth factor receptor alpha (PDGFRα) or high PDGFRβ expression in in vitro assays to investigate the specific downstream effects of nilotinib treatment. Using in vitro cell-based assays we show that nilotinib inhibits PDGF-BB-dependent activation of PDGFRα. We further show that nilotinib is able to decrease cell proliferation and anchorage-independent growth via suppression of AKT and ERK1/2 signaling pathways. Our results suggest that nilotinib may be effective for management of a PDGFRα-dependent group of pediatric gliomas.
The Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, University of Toronto, Toronto, ON, M5G 1L7, Canada.
Karolyn
K
Au
Sanjay K
SK
Singh
Kelly
K
Burrell
Nesrin
N
Sabha
Cynthia
C
Hawkins
Annie
A
Huang
Gelareh
G
Zadeh
D000818:Animals; D000077214:Becaplermin; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003114:Colony-Forming Units Assay; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005910:Glioma / Q000188:drug therapy / Q000473:pathology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D016513:Mice, SCID; D051058:Oncogene Protein v-akt / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D013997:Time Factors; D016596:Vinculin / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D004791:Enzyme Inhibitors; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines; D016596:Vinculin; D000077214:Becaplermin; D020796:Receptor, Platelet-Derived Growth Factor alpha; D051058:Oncogene Protein v-akt; C498826:nilotinib