Last week the highly productive, DIPG-focused Netherlands group from VU University Medical Center in Amsterdam put forth another publication which happens to have free full text available!
This research focuses on unravelling the reasons why chemotherapy has not been beneficial against DIPGs and pediatric high-grade gliomas. Are DIPGs just resistant to the agents? Or, is it that something is protecting the cells which causes an otherwise good option to be ineffective?
Part 1- Are glioma cells just resistant to chemotherapy?
To look at the first question, the researchers evaluated 9 pediatric glioma cell lines to eliminate questions of adequate drug delivery. Three of these cell lines were from children with DIPGs and 6 were from supratentorial high grade gliomas. Of the 3 DIPG cell lines, all were of different histologic grades- one GBM, one anaplastic astrocytoma and one diffuse fibrillary asrocytomas. Two of these DIPG cell lines came from children who had not had any treatment. The other cell line came from an autopsy donation done approximately 2 hours after death.
In the screening of these cell lines, several agents had high level of killing tumor cells.
When looking at targeted small molecule agents, these did not fare as well as classical chemotherapies. Some did show some efficacy . The best of these was bortezomib which resulted in more than 50% reduction in cell line surival in 6/9 cell lines. There was little or no effect with erlotinib and everolimus. A hypothesis for this result include that the cell lines were not checked for the targets. If there was a matching of targets and agents the results might have been better. Also since there are multiple messed up pathways combined therapy is generally thought to be needed and a single agents is very unlikely to be effective.
In looking at classic chemotherapy agents, melphalan was the only drug that had significiant toxicity in all cell lines. Interestly that is the exact agent of the new intra-arterial Hopkins DIPG trial!
Other agents that were found to have a signficant effect included doxorubicin, mitoxantrone and BCNU. The next level included etoposide, thiotepa and carboplatin. Carboplatin was of special note since that is what the UK in their CED report.
What this means for DIPG is that DIPG is not necessarily resistant to chemotherapy! Effective drgus might not be the biggest hurdle for a cure for DIPG. It might be getting them to the tumor cells.
This work was funded by KiKa "Stichting Kinderen Kankervrij"- Dutch Children Cancer-free Foundation.
Tomorrow.....
Part 2- Do the efflux transporters protect the glioma cells?
References:
In vitro drug response and efflux transporters associated with drug resistance in pediatric high grade glioma and diffuse intrinsic pontine glioma
PLoS One. 2013 Apr 29;8(4):e61512. doi: 10.1371/journal.pone.0061512. Print 2013.
Free Full Text- http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3639279/
KiKa Stichting Kinderen Kankervrij- Dutch Children Cancer-free Foundation
http://www.kika.nl/
