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

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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.

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Most cited references 50

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The landscape of genomic alterations across childhood cancers

Susanne N. Gröbner, Barbara C. Worst, Joachim Weischenfeldt … (2018)

Pan-cancer analyses that examine commonalities and differences among various cancer types have emerged as a powerful way to obtain novel insights into cancer biology. Here we present a comprehensive analysis of genetic alterations in a pan-cancer cohort including 961 tumours from children, adolescents, and young adults, comprising 24 distinct molecular types of cancer. Using a standardized workflow, we identified marked differences in terms of mutation frequency and significantly mutated genes in comparison to previously analysed adult cancers. Genetic alterations in 149 putative cancer driver genes separate the tumours into two classes: small mutation and structural/copy-number variant (correlating with germline variants). Structural variants, hyperdiploidy, and chromothripsis are linked to TP53 mutation status and mutational signatures. Our data suggest that 7-8% of the children in this cohort carry an unambiguous predisposing germline variant and that nearly 50% of paediatric neoplasms harbour a potentially druggable event, which is highly relevant for the design of future clinical trials.

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Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma.

P. Lewis, M. Müller, M. Koletsky … (2013)

Sequencing of pediatric gliomas has identified missense mutations Lys27Met (K27M) and Gly34Arg/Val (G34R/V) in genes encoding histone H3.3 (H3F3A) and H3.1 (HIST3H1B). We report that human diffuse intrinsic pontine gliomas (DIPGs) containing the K27M mutation display significantly lower overall amounts of H3 with trimethylated lysine 27 (H3K27me3) and that histone H3K27M transgenes are sufficient to reduce the amounts of H3K27me3 in vitro and in vivo. We find that H3K27M inhibits the enzymatic activity of the Polycomb repressive complex 2 through interaction with the EZH2 subunit. In addition, transgenes containing lysine-to-methionine substitutions at other known methylated lysines (H3K9 and H3K36) are sufficient to cause specific reduction in methylation through inhibition of SET-domain enzymes. We propose that K-to-M substitutions may represent a mechanism to alter epigenetic states in a variety of pathologies.

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Genome-wide analyses identify recurrent amplifications of receptor tyrosine kinases and cell-cycle regulatory genes in diffuse intrinsic pontine glioma.

Chunxu Qu, Stuart N. Baker, Arzu Onar-Thomas … (2011)

Long-term survival for children with diffuse intrinsic pontine glioma (DIPG) is less than 10%, and new therapeutic targets are urgently required. We evaluated a large cohort of DIPGs to identify recurrent genomic abnormalities and gene expression signatures underlying DIPG. Single-nucleotide polymorphism arrays were used to compare the frequencies of genomic copy number abnormalities in 43 DIPGs and eight low-grade brainstem gliomas with data from adult and pediatric (non-DIPG) glioblastomas, and expression profiles were evaluated using gene expression arrays for 27 DIPGs, six low-grade brainstem gliomas, and 66 nonbrainstem low-grade gliomas. Frequencies of specific large-scale and focal imbalances varied significantly between DIPGs and nonbrainstem pediatric glioblastomas. Focal amplifications of genes within the receptor tyrosine kinase-Ras-phosphoinositide 3-kinase signaling pathway were found in 47% of DIPGs, the most common of which involved PDGFRA and MET. Thirty percent of DIPGs contained focal amplifications of cell-cycle regulatory genes controlling retinoblastoma protein (RB) phosphorylation, and 21% had concurrent amplification of genes from both pathways. Some tumors showed heterogeneity in amplification patterns. DIPGs showed distinct gene expression signatures related to developmental processes compared with nonbrainstem pediatric high-grade gliomas, whereas expression signatures of low-grade brainstem and nonbrainstem gliomas were similar. DIPGs comprise a molecularly related but distinct subgroup of pediatric gliomas. Genomic studies suggest that targeted inhibition of receptor tyrosine kinases and RB regulatory proteins may be useful therapies for DIPG.

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Author and article information

Journal

Title: Neurosurgery

Publisher: Oxford University Press (OUP)

ISSN (Print): 0148-396X

ISSN (Electronic): 1524-4040

Publication date Created: May 2020

Publication date Created: May 01 2020

Publication date Created: June 21 2019

Publication date Other: May 2020

Publication date (Print): May 01 2020

Publication date (Electronic): June 21 2019

Volume: 86

Issue: 5

Pages: 742-751

Affiliations

[1 ]Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina

[2 ]Department of Neurosurgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois

[3 ]Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina

[4 ]Department of Radiology, Duke University Medical Center, Durham, North Carolina

[5 ]Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany

[6 ]Department of Pediatric Neuro-Oncogenomics, German Cancer Consortium and German Cancer Research Center, Heidelberg, Germany

[7 ]University of North Carolina School of Medicine, Chapel Hill, North Carolina

[8 ]Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois

[9 ]Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois

[10 ]Duke University Preston Robert Tisch Brain Tumor Center, Durham, North Carolina

Article

DOI: 10.1093/neuros/nyz212

PubMed ID: 31225627

SO-VID: 3cc9c620-fbe9-4caf-ab0a-37ee2f8b61b5

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https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model

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

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Abstract

BACKGROUND

OBJECTIVE

METHODS

RESULTS

CONCLUSION

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Most cited references 50

The landscape of genomic alterations across childhood cancers

Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma.

Genome-wide analyses identify recurrent amplifications of receptor tyrosine kinases and cell-cycle regulatory genes in diffuse intrinsic pontine glioma.

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