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      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 references6

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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.
          Article 0 comments Cited 451 times – based on 0 reviews     Review now
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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.
            Article 0 comments Cited 286 times – based on 0 reviews     Review now
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              Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations

              Pawel Buczkowicz, Christine Hoeman, Patricia Rakopoulos … (2014)
              Diffuse Intrinsic Pontine Glioma (DIPG) is a fatal brain cancer that arises in the brainstem of children with no effective treatment and near 100% fatality. The failure of most therapies can be attributed to the delicate location of these tumors and choosing therapies based on assumptions that DIPGs are molecularly similar to adult disease. Recent studies have unraveled the unique genetic make-up of this brain cancer with nearly 80% harboring a K27M-H3.3 or K27M-H3.1 mutation. However, DIPGs are still thought of as one disease with limited understanding of the genetic drivers of these tumors. To understand what drives DIPGs we integrated whole-genome-sequencing with methylation, expression and copy-number profiling, discovering that DIPGs are three molecularly distinct subgroups (H3-K27M, Silent, MYCN) and uncovering a novel recurrent activating mutation in the activin receptor ACVR1, in 20% of DIPGs. Mutations in ACVR1 were constitutively activating, leading to SMAD phosphorylation and increased expression of downstream activin signaling targets ID1 and ID2. Our results highlight distinct molecular subgroups and novel therapeutic targets for this incurable pediatric cancer.
              Article 0 comments Cited 150 times – based on 0 reviews     Review now
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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
                Copyright © © 2019
                License:

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

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