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.
Highlights
Pediatric high grade glioma constitutes 15–20% of pediatric central nervous system tumors [1]
Multidrug Resistant Protein 1 (MRP1) is expressed in glioma cells. These findings suggest that the presence of all three major drug efflux pumps in the bloodbrain-barrier (BBB) may form a first line of resistance of Pediatric high grade glioma (pHGG) to treatment with classic chemotherapeutic drugs which by themselves are capable of inducing cytotoxicity in pediatric glioma cells
- to our knowledge - we provide the first data on drug sensitivity screening of primary Diffuse intrinsic pontine glioma (DIPG) cultures, suggesting that DIPG per se is not necessarily resistant to chemotherapy
Summary
Pediatric high grade glioma (pHGG) constitutes 15–20% of pediatric central nervous system tumors [1]. These aggressive tumors are difficult to treat, and are associated with an extremely poor prognosis. Diffuse intrinsic pontine glioma (DIPG), an infiltrative tumor typically originating in the pons, does not qualify for surgical resection due to its delicate location. No chemotherapeutical regimens or alternative radiation options have successfully improved OS or PFS in children with HGG and DIPG [4,5]. These disappointing results emphasize the need to identify effective drugs. We screened a heterogeneous group of primary pHGG cell cultures, including three DIPG cultures, for their sensitivity in vitro to different drugs
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