ABCG2 AND MDR PROMOTE BRAINSTEM GLIOMAGENESIS AND LIMIT THE EFFICACY OF DASATINIB IN A DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) MOUSE MODEL

摘要

BACKGROUND: DIPG is an incurable tumor that arises in the brainstem of children. Our laboratory generates murine DIPGs by expressing PDGF-B and deleting p53 in nestin progenitors of the neonatal brainstem using the RCAS/tv-a system. Dasatinib, an inhibitor of PDGFR-A and SRC activation, has been evaluated in clinical trials for children with DIPG but with disappointing results. As dasatinib is a substrate of the ABC transporters ABCG2 and MDR, we hypothesized that ABCG2 and MDR may limit the efficacy of dasatinib in DIPG. METHODS: We generated murine DIPGs driven by PDGF-B and p53 loss in ABC WT (ABCG2+/+; MDRa+/+; MDRb+/+) and ABC KO (ABCG2-/-; MDRa-/-; MDRb-/-) mice. Next, we investigated whether dasatinib is efficacious in ABC KO and ABC WT DIPG-bearing mice. We treated ABC WT DIPG-bearing mice with dasatinib alone, elacridar (a dual ABCG2/MDR inhibitor) alone, and dasatinib in combination with elacridar. We also measured dasatinib levels in the tumor and plasma of all of the different tumor cohorts. Lastly, we evaluated the blood-brain-barrier (BBB) of our DIPG mouse model with Dextran Texas Red. RESULTS: Surprisingly, we observed a significant difference in tumor latency between untreated ABC KO and untreated ABC WT mice in this PDGF-B; p53 deficient DIPG model. Median survival of DIPG-bearing ABC KO was longer than DIPG-bearing ABC WT: 43 days vs. 34 days respectively (p = 0.02). We observed that dasatinib almost doubled the survival of DIPG-bearing mice in the ABC KO model: 44 days vs. 80 days (p = 0.0004). Dasatinib modestly prolonged survival in ABC WT mice: 33 days vs. 42 days (p < 0.0001). Co-treatment with elacridar significantly increased the efficacy of dasatinib in the ABC WT model 42 days vs. 59 days (p < 0.0001). However, elacridar alone did not significantly prolong survival in the ABC WT mice 33 days vs. 34 days (p = 0.38). Pharmacokinetic analysis demonstrated that genetic ablation of the ABC transporters or inhibition of ABC transporters with elacridar significantly increased dasatinib delivery into normal brain but not into tumor. Dextran Texas Red studies demonstrated a disrupted BBB in DIPG models independent of ABC transporters. CONCLUSIONS: 1. ABC transporters promote brainstem gliomagenesis 2. ABC transporters regulate dasatinib delivery into normal brain but not into the tumor as BBB is disrupted in our DIPG mouse model 3. ABC transporter activity limits the efficacy of dasatinib in vivo. Our results suggest that ABCG2 and MDR inhibitors may have a therapeutic role in the treatment of DIPG. SECONDARY CATEGORY: Preclinical Experimental Therapeutics.