1. Combined Therapy of AXL and HDAC Inhibition Reverses Mesenchymal Transition in Diffuse Intrinsic Pontine Glioma.
- Author
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Meel MH, de Gooijer MC, Metselaar DS, Sewing ACP, Zwaan K, Waranecki P, Breur M, Buil LCM, Lagerweij T, Wedekind LE, Twisk JWR, Koster J, Hashizume R, Raabe EH, Montero Carcaboso Á, Bugiani M, Phoenix TN, van Tellingen O, van Vuurden DG, Kaspers GJL, and Hulleman E
- Subjects
- Animals, Benzocycloheptenes pharmacology, Biomarkers, Tumor, Blood-Brain Barrier drug effects, Blood-Brain Barrier metabolism, Cell Line, Tumor, Combined Modality Therapy, Diffuse Intrinsic Pontine Glioma drug therapy, Diffuse Intrinsic Pontine Glioma etiology, Disease Models, Animal, Drug Synergism, Epithelial-Mesenchymal Transition drug effects, Epithelial-Mesenchymal Transition genetics, Histone Deacetylase Inhibitors therapeutic use, Humans, Immunohistochemistry, Mice, Protein Kinase Inhibitors therapeutic use, Triazoles pharmacology, Xenograft Model Antitumor Assays, Axl Receptor Tyrosine Kinase, Diffuse Intrinsic Pontine Glioma metabolism, Diffuse Intrinsic Pontine Glioma pathology, Histone Deacetylase Inhibitors pharmacology, Histone Deacetylases metabolism, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins antagonists & inhibitors, Receptor Protein-Tyrosine Kinases antagonists & inhibitors
- Abstract
Purpose: Diffuse intrinsic pontine glioma (DIPG) is an incurable type of pediatric brain cancer, which in the majority of cases is driven by mutations in genes encoding histone 3 (H3K27M). We here determined the preclinical therapeutic potential of combined AXL and HDAC inhibition in these tumors to reverse their mesenchymal, therapy-resistant, phenotype., Experimental Design: We used public databases and patient-derived DIPG cells to identify putative drivers of the mesenchymal transition in these tumors. Patient-derived neurospheres, xenografts, and allografts were used to determine the therapeutic potential of combined AXL/HDAC inhibition for the treatment of DIPG., Results: We identified AXL as a therapeutic target and regulator of the mesenchymal transition in DIPG. Combined AXL and HDAC inhibition had a synergistic and selective antitumor effect on H3K27M DIPG cells. Treatment of DIPG cells with the AXL inhibitor BGB324 and the HDAC inhibitor panobinostat resulted in a decreased expression of mesenchymal and stem cell genes. Moreover, this combination treatment decreased expression of DNA damage repair genes in DIPG cells, strongly sensitizing them to radiation. Pharmacokinetic studies showed that BGB324, like panobinostat, crosses the blood-brain barrier. Consequently, treatment of patient-derived DIPG xenograft and murine DIPG allograft-bearing mice with BGB324 and panobinostat resulted in a synergistic antitumor effect and prolonged survival., Conclusions: Combined inhibition of AXL and HDACs in DIPG cells results in a synergistic antitumor effect by reversing their mesenchymal, stem cell-like, therapy-resistant phenotype. As such, this treatment combination may serve as part of a future multimodal therapeutic strategy for DIPG., (©2020 American Association for Cancer Research.)
- Published
- 2020
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