Dipg-04. Inhibition of Axl Sensitizes Diffuse Intrinsic Pontine Glioma to Cytotoxic Therapies
Year: 2018
Type: conference-abstract
Abstract: Diffuse intrinsic pontine glioma (DIPG) is an incurable type of pediatric brainstem cancer that is thought to originate from primitive neural stem cells, and is characterized by the frequent presence of mutations in histone 3 genes. Biopsy studies have shown that a large subset of DIPG possesses a mesenchymal phenotype, likely contributing to the diffuse growth pattern and inherent therapy resistance of these tumors. Recently, the receptor tyrosine kinase AXL has been identified both as an important player in the mesenchymal transition and as a hallmark of neural stem cells. In this study, we demonstrate that AXL is a driver of the mesenchymal and stem-like phenotype of DIPG cells and as such, is a promising therapeutic target. Inhibition of AXL by the small molecule BGB324, in combination with the HDAC inhibitor panobinostat, potently and synergistically decreases cell viability and migration of primary DIPG cultures, and reverses their mesenchymal and stem-like phenotype. Moreover, this combination treatment leads to decreased expression of important genes involved in DNA repair, and a strong radiosensitizing effect on DIPG cultures. Pharmacokinetic studies further reveal that BGB324 is capable of crossing the blood-brain barrier and can reach therapeutic concentrations in mouse brain. Consequently, we demonstrate that treatment of DIPG xenograft bearing mice with BGB324 and panobinostat results in a decrease in tumor load and extended survival. Altogether, our study shows that AXL is an important player in DIPG biology and demonstrates the promising therapeutic potential of the combination of BGB324 and panobinostat for the treatment of DIPG.
Source: Neuro-Oncology
Authors: Michaël Meel, Mark de Gooijer, Kenn Zwaan, Piotr Waranecki, Marjolein Breur, Levi Buil, Tonny Lagerweij, Laurine Wedekind, Jos Twisk, Jan Koster, Rintaro Hashizume, Eric Raabe, Ángel Montero Carcaboso, Marianna Bugiani, Olaf van Tellingen, Dannis van Vuurden, Gertjan Kaspers, Esther Hulleman
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2809162928