A preclinical study demonstrating the efficacy of nilotinib in inhibiting the growth of pediatric high-grade glioma

Karolyn Au,Cynthia Hawkins,Kelly Burrell,Gelareh Zadeh,Annie Huang,Nesrin Sabha,Sanjay K Singh

doi:10.1007/s11060-015-1744-y

Abstract

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.Electronic supplementary materialThe online version of this article (doi:10.1007/s11060-015-1744-y) contains supplementary material, which is available to authorized users.

Highlights

Malignant glial neoplasms comprise 8–10 % of primary pediatric central nervous system (CNS) tumors [1], and are the most common cause of solid tumor-related death in children [2]
We found that normal human astrocytes (NHA) expressed PDGFRb but not platelet-derived growth factor receptor alpha (PDGFRa)
Recognizing that understanding of this disease and advancement of therapy has historically been hindered by reliance upon studies of adult gliomas, we have carried out investigations of PDGFRa signaling and inhibition in cell lines derived from pediatric glioblastoma tumors

Summary

Introduction

Malignant glial neoplasms comprise 8–10 % of primary pediatric central nervous system (CNS) tumors [1], and are the most common cause of solid tumor-related death in children [2]. These lesions are classified as grade III or IV by the World Health Organization (WHO), and histology is most commonly anaplastic astrocytoma (AA; grade III) and glioblastoma (GBM; grade IV) [3]. Several exome sequencing profiles of high-grade pediatric supratentorial and brainstem gliomas revealed a frequent, novel mutation of H3F3A, encoding histone variant H3.3, that is associated with poorer overall survival [8, 9]; among brainstem lesions, amplification of PDGFRA occurred exclusively in H3F3A-mutant tumors [10].

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Results

Conclusion