ABC Transporter Inhibition Plus Dexamethasone Enhances the Efficacy of Convection Enhanced Delivery in H3.3K27M Mutant Diffuse Intrinsic Pontine Glioma

Abstract

BACKGROUND An impermeable blood–brain barrier and drug efflux via ATP-binding cassette (ABC) transporters such as p-glycoprotein may contribute to underwhelming efficacy of peripherally delivered agents to treat diffuse intrinsic pontine glioma (DIPG). OBJECTIVE To explore the pharmacological augmentation of convection-enhanced delivery (CED) infusate for DIPG. METHODS The efficacy of CED dasatinib, a tyrosine kinase inhibitor, in a transgenic H3.3K27M mutant murine model was assessed. mRNA expression of ABCB1 (p-glycoprotein) was analyzed in 14 tumor types in 274 children. In Vitro viability studies of dasatinib, the p-glycoprotein inhibitor, tariquidar, and dexamethasone were performed in 2 H3.3K27M mutant cell lines. Magnetic resonance imaging (MRI) was used to evaluate CED infusate (gadolinium/dasatinib) distribution in animals pretreated with tariquidar and dexamethasone. Histological assessment of apoptosis was performed. RESULTS Continuous delivery CED dasatinib improved median overall survival (OS) of animals harboring DIPG in comparison to vehicle (39.5 and 28.5 d, respectively; P = .0139). Mean ABCB1 expression was highest in K27M gliomas. In Vitro, the addition of tariquidar and dexamethasone further enhanced the efficacy of dasatinib (P < .001). In Vivo, MRI demonstrated no difference in infusion dispersion between animals pretreated with dexamethasone plus tariquidar prior to CED dasatinib compared to the CED dasatinib. However, tumor apoptosis was the highest in the pretreatment group (P < .001). Correspondingly, median OS was longer in the pretreatment group (49 d) than the dasatinib alone group (39 d) and no treatment controls (31.5 d, P = .0305). CONCLUSION ABC transporter inhibition plus dexamethasone enhances the efficacy of CED dasatinib, resulting in enhanced tumor cellular apoptosis and improved survival in H3.3K27M mutant DIPG.

Real-time sensing of MAPK signaling in medulloblastoma cells reveals cellular evasion mechanism counteracting dasatinib blockade of ERK activation during invasion

“…Hence, coupling of dasatinib to α v integrin-directed cRGD silica nanoparticles, which facilitates drug passage across the partially disrupted BBB in a murine GBM model, may be necessary for increasing the accumulation, retention, and diffusion of the drug [46] . An alternative strategy is convection-enhanced delivery of dasatinib in combination with the ABC transporter inhibitor tariquidar and dexamethasone, which enhanced tumor cell apoptosis and survival in a mouse model of H3.3K27M mutant diffuse intrinsic pons glioma [47] . However, the effect of dasatinib to promote a mesenchymal to amoeboid transition in a subset of cells calls for cautious monitoring of therapeutic benefits, in particular with respect to the consequence of drug treatment on local infiltration at primary and metastatic sites.…”

Targeting and Therapeutic Monitoring of H3K27M-Mutant Glioma

“…Currently open phase 1/2 trials utilizing CED in DIPG include a study of a panobinostat nanoparticle formulation along with gadoteridol in newly diagnosed DIPG patients, as well as a trial delivering nanoliposomal irinotecan following radiotherapy [59,60]. A study open since 2011 has utilized CED to deliver a radionucleotide-antibody complex that targets the B7-H3 antigen commonly expressed by DIPG [61]. While promising, many issues remain in wider use of CED in DMG.…”

ABC Transporters at the Blood–Brain Interfaces, Their Study Models, and Drug Delivery Implications in Gliomas

“…They can be co-administered with drugs to evaluate if their BBB permeability is restricted by ABC transporters, to image the transporters' function [262], or to evaluate their substrate or inhibitor interactions with ABC transporters [130], and new inhibitors are continuously under development. Furthermore, promising results have been observed when combined with other strategies for bypassing the BBB such as convection enhanced delivery [373] (Section 6.4) and nanoparticles or targeting nanocarriers (Section 6.6) [374]. Therefore, it is worthwhile to summarize them in this section.…”

“…The use of ABC inhibitors has been suggested as a strategy to improve CED and could be further explored. For instance, a recent study showed an improvement of tumor apoptosis in a transgenic H3.3K27M mutant murine model of diffuse intrinsic pontine glioma by a pretreatment of dexamethasone plus tariquidar before convection-enhanced delivery (Section 6.5) of dasatinib [373].…”