Novel therapies for diffuse intrinsic pontine glioma

Abstract

Diffuse intrinsic pontine glioma (DIPG), a paediatric high-grade glioma originating in the pons, is one of the most aggressive paediatric cancers with a historically dismal outcome. Radiation therapy (RT) is the only treatment modality available but is not curative. In spite of hundreds of clinical trials, no effective treatment has been identified so far. Recently, there has been an exponential increase in preclinical research involving DIPG, and many, previously unknown, molecular aberrations that contribute to DIPG pathogenesis have been identified. This research represents the first report to highlight the cytotoxic activity of fenretinide against DIPG cells. Fenretinide was effective in vitro across a panel of DIPG cell lines. Our DIPG cell lines were characterized by the absence of retinoic acid receptor expression which may explain the lack of activity of other retinoids. We were able to demonstrate that fenretinide’s cytotoxicity was related to apoptosis induction secondary to ROS production and caspase activation. Importantly, we identified a previously unrecognized mechanism of action of fenretinide in the form of inhibition of PDGFR transcription implying an action similar to RTK inhibition. In vivo experiments confirmed fenretinide activity against DIPG. In addition, we demonstrated promising synergy of fenretinide in combination with ponatinib and irradiation. Lastly, on combination HTS, we identified some exciting drug combinations. These drugs are from diverse classes like anticancer drugs as well as antimicrobial and antimalarial agents but interestingly demonstrated good DIPG inhibitory activity. Thus, discovery of novel combination agents, with anti-tumour activity may be potentially effective in DIPG.