In Vitro Drug Response and Efflux Transporters Associated with Drug Resistance in Pediatric High Grade Glioma and Diffuse Intrinsic Pontine Glioma

Abstract

Pediatric high-grade gliomas (pHGG), including diffuse intrinsic pontine gliomas (DIPG), are the leading cause of cancer-related death in children. While it is clear that surgery (if possible), and radiotherapy are beneficial for treatment, the role of chemotherapy for these tumors is still unclear. Therefore, we performed an in vitro drug screen on primary glioma cells, including three DIPG cultures, to determine drug sensitivity of these tumours, without the possible confounding effect of insufficient drug delivery. This screen revealed a high in vitro cytotoxicity for melphalan, doxorubicine, mitoxantrone, and BCNU, and for the novel, targeted agents vandetanib and bortezomib in pHGG and DIPG cells. We subsequently determined the expression of the drug efflux transporters P-gp, BCRP1, and MRP1 in glioma cultures and their corresponding tumor tissues. Results indicate the presence of P-gp, MRP1 and BCRP1 in the tumor vasculature, and expression of MRP1 in the glioma cells themselves. Our results show that pediatric glioma and DIPG tumors per se are not resistant to chemotherapy. Treatment failure observed in clinical trials, may rather be contributed to the presence of drug efflux transporters that constitute a first line of drug resistance located at the blood-brain barrier or other resistance mechanism. As such, we suggest that alternative ways of drug delivery may offer new possibilities for the treatment of pediatric high-grade glioma patients, and DIPG in particular.

Managing teenage/young adult (TYA) brain tumors: a UK perspective

“…Similar disappointing results have been found with other chemotherapy combinations [44,45]. It has been demonstrated in vitro that DIPG cells are not technically chemotherapy resistant, but rather express drug efflux transporters extracellularly [46]. This may provide a focus for further research and a potential treatment paradigm.…”

Effects of temozolomide (TMZ) on the expression and interaction of heat shock proteins (HSPs) and DNA repair proteins in human malignant glioma cells

“…The lack of success in the results may be at least partly explained by the inability to deliver therapeutic agents to the CNS tumors across the blood-brain barrier (Laquintana et al 2009). Drug delivery to the brain is hampered by the presence of P-glycoprotein (P-gp, ABCB1), breast cancer resistance protein (BCRP, ABCG2), and multidrug resistance-associated proteins (MRPs, ABCC1) (Veringa et al 2013). In glioma cell lines, MDR1 Pglycoprotein and ABCC1 were shown to confer resistance to various anticancer drugs (Spiegl-Kreinecker et al 2002;Bronger et al 2005).…”

Phase I study of non-pegylated liposomal doxorubicin in children with recurrent/refractory high-grade glioma

“…Clinical studies showed that in adults, Myocet ® has a longer half-life than standard doxorubicin, significantly less cardiotoxicity, and comparable antitumour efficacy [3,4].…”

“…The brain exposure to this drug is, however, hindered by the bloodbrain barrier. Encapsulation of DXR in liposomal carriers has been shown to both reduce toxicities [3,4] and improve brain tumour exposure to doxorubicin [5]. Moreover, while…”