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Tuesday, May 7, 2013

Part 2- Do the efflux transporters protect the glioma cells?

One of the longstanding questions for DIPG has been."Why doesn't chemo work?"
There have been dozens of trials using all kinds of agents and all of them have virtually the identical Kaplan Meier Curve.  The think we don't know is why that is.   Often times one hears about something in the blood brain barrier that limits chemotherapy effectiveness.   Other times one wonders if it is something in the glioma cells themselves that make them more resistant.   The Netherlands paper tried to answer one part of this in better defining ABC transporters in pediatric glioma.

ABC transporters essentially function as little door ways in the cell's membrane either usher substances into the cell (importers) or out of the cells (exporters).   The exporters are tone ones that are a problem withe drug resistance.   The transporters pump drugs and toxins out of the cells.

There have been 3 different ABC transporters found that escort drugs out of cells.   These include P-glcyoprotein (P-gp, ABCB1), breast cancer resistance protein (BCRP, ABCG2) and multidrug resistance associated proteins (MRPs, ABCC1).

This Netherlands study looked at the above 3 ABC transporters in each of the glioma cell lines.   All cell lines were negative for P-gp.  Only one supratentorial pediatric glioma cell line had BRCP1.  High levels of MRP1 was found in 4 of the 9 glioma cell lines.  That included 2 of 3 of the DIPG cell lines.

 The researchers then looked at actual tumor sample sections to try to determine the amount of ABC transporters in the glioma cells versus the blood vessels. They found that P-gp was not present in most of the glioma cells but was presesnt moderately in the tumor's blood vessels.   BCRP1 was not present in the glioma cells but was highly pressent in the blood vessels. Only MRP1 was seen in both the glioma cells and the blood vessels.   A chart on the cell lines tested (including 2 of the 3 DIPG samples) is available (click here to see chart).

So, what does this mean for DIPG now?

That is hard to say.   So far tying to inhibit the ABC transporters with different agents have been problematic because of significant toxic side effects.   These ABC transporters are meant to protect normal cells as well.   However, since  most of the ABC transporters seem to be in the blood vessels  a way around this blood-brain barrier could be direct tumor delivery (i.e., convenction enhanced delivery).  The researchers also suggest developing drugs that are not a substract for these transporters could also increase chemotherapy effectiveness.

It does tell us that in trying to find a cure for DIPG that we can not just focus on finding targets within the cancer biology but also need to work on finding ways for new agents to be able reach these targets.

Note:  The ATP-binding cassette transporters issue was featured in a recent blogspot regarding a new abstract out of Oren Becher's lab in Duke.

This work was funded by KiKa "Stichting Kinderen Kankervrij"- Dutch Children Cancer-free Foundation.

In vitro drug response and efflux transporters associated with drug resistance in pediatric high grade glioma and diffuse intrinsic pontine glioma
 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

ABC transporters limit dansantinib efficacy in mice