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Saturday, April 20, 2013

ABC transporters limit dasatinib efficacy in mice

Ever since the first whole genome DIPG profile paper from Sick Kids in Canada came out in 2010, there has been interest in platelet derived growth factor receptor alpha.  This is because all the samples (9 post-mortem and two pretreated surgical samples) showed PDGRF-alpha expression.  The hope was that PDGFR-alpha could be a target to make a difference in DIPG.   The search was on for an agent to try.

An available PDGFR-alpha antagionist was found, dasantinib.  This Bristol-Myers-Squibb drug is marketed under the name Sprycel for the indication chronic myelogenous leukemia (CML).  When looking in clinicaltrials.gov, there are already 219 trials up for this drug.  It has been already been tried on adults and in children.   The availability and prior use seemed to make this drug easily translatable to trials for DIPG kids.  St. Jude has completed one trials using dasatinib and vandetanib and another open trial using dasatinib and crizotinib.

The thing about dasatinib is that it seems that it can be pumped out a a cell because by ABC (ATP-binding cassette) transporters.   This is a "superfamily" of  proteins that transport things (such as sugars, lipids, toxins and drugs) across the cell membranes.  Three of these ABC transporters are known to cause chemoresistance.  These are MDR, ABDG2 and ABCB1.  Datinib is known to be a substrate for MDR and ABCG2.

An abstract from Oren Becher's lab at Duke is going to be presented at the SNO/PBTF Pediatric Neuro-Oncology Basic and Translational Research Conference next month in Fort Lauderdale looking at whether altering these transport proteins can alter dasatinib activity.   They did this by making DIPG mouse models that were deficient in the transporters ABCG2 and MDR.  At the first signs of tumor, these mice were given dasantinib.  The mice were sacrified a day later and the brains examined for specific things (caspase-3 and phospho-histone H3).

There was no difference in phosoph-histone H3 whether the transporter was present or not in the mice. However,  mice without the transporter had a 20 fold increase in caspace C levels as compared to those mice with the transporter.

These researchers concluded that these ABC transporters impact dasatinib's efficacy.  Further study is need to see if transporter-deficient mice can live longer when treated with dasatinib and if a transporter inhibitor (such as elacridar) can increase efficacy hopefully increasing survival.

ABC transporters, ABCG2 and MDR, limit the efficacy of dasatinib in a diffuse intrinsic pontine glioma (DIPG) mouse model

Brain distribution and bioavailability of elacridar after different routes of administration in the mouse

Oren Becher Lab at Duke

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