Hg-25fenretinide Targets the Rtk-pi3k Pathway in Diffuse Intrinsic Pontine Glioma (dipg)
Year: 2016
Type: article
Abstract: With 250 failed clinical trials for DIPG, there is an urgent need for the rational development of evidence based novel therapies. We initiated a national, Australian DIPG autopsy protocol, and successfully established DIPG neurosphere cultures. A high-throughput drug screen (HTS) with over 3500 FDA-approved compounds was performed against DIPG neurospheres. Hits were prioritized based on their ability to cross the blood brain barrier, activity across a panel of DIPG cultures, and specificity for DIPG compared with non-malignant cells. Based on these criteria, fenretinide - a synthetic retinoid - was one of the top 5 compounds identified. Our in-vitro cytotoxicity assays showed that fenretinide had potent activity against a panel of DIPG neurosphere cultures with an IC50 of 1-2 µM. Mechanism of action studies showed that fenretinide acted independent of retinoic acid receptors to induce activation of the apoptotic pathway. Further studies showed this action was modulated by inhibition of the aberrantly activated RTK-PI3K pathway. To augment the activity of fenretinide, combination studies were performed with other pro-apoptotic agents and receptor tyrosine kinase inhibitors. Ponatinib is a pro-apoptotic, multi-targeted tyrosine kinase inhibitor that showed significant synergistic activity in combination with fenretinide. The combination therapy led to enhanced cytotoxicity with increased apoptotic death of DIPG cells. This therapy is currently being evaluated in an orthotopic DIPG animal model. We have identified a rational novel and potentially effective combination strategy for treatment of DIPG that can be rapidly translated to the clinic.
Source: Neuro-Oncology
Language: English
Subfield: Genetics (clinical)
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2424430917