New Investigator Grant Awarded to Matt Dun

A number of promising experimental treatment agents are currently under intensive investigation around the world, however patients diagnosed with DIPG still succumb quickly. Current survival is thought to be slightly longer than the 10 months previously accepted as the average survival post-diagnosis, with some responders when treated upfront with these novel agents living more than 18 months. For the first time, this small extension in patient survival confirms that pharmacological inhibition of DIPG growth is possible, which provides us with the opportunity to increase duration and durability of response by increasing our understanding of how DIPG tumors overcome the therapeutic challenge posed by these non-toxic, oral, targeted therapies. Therapies such as ONC201 and GDC-0084 target cellular growth and survival pathways commonly over activated in a number of cancers, are currently under clinical trial for both glioblastoma multiforme (GBM) and DIPG. Although we await the official results of these investigations, both agents have been deemed to have suitable safety profiles, and increased survival is predicted. Following my then 2-year-old daughter, Josephine, being diagnosed with DIPG (2/2018), my laboratory has spent 18 months subjecting both GDC-0084 and ONC201 to rigorous preclinical testing. Josie's DIPG tumor harbors a number of mutations suggestive of responsiveness to GDC-0084 (PIK). Following clinical and radiological signs of disease progression in November 2018, Josie became the first child worldwide to receive GDC-0084, thanks to compassionate access supported by our own laboratory findings. Josephine remains on GDC-0084 in combination with ONC-201 to this day (11 months). Our studies have shown GDC-0084 is effective against all DIPG cell lines tested (n=10), regardless of their individual mutations. GDC-0084 provides a modest but significant survival advantage in a DIPG mouse model (a model developed to confirm GDC-0084 reaches the brainstem) and interestingly, we see absolutely no cytotoxicity in a normal human endothelial cell blood brain barrier (BBB) model we have developed to study the transit of drugs into the brainstem. This contrasts with our studies using ONC201; where 5/8 DIPG cell lines show some level of sensitivity, however the molecular basis of resistance is unknown. This project will reveal ways to improve response to GDC-0084 and ONC-201 by studying the cellular response (phosphoproteomic profiling) to pharmacological challenge using patient cell lines and samples obtained thanks to our collaborators in Zurich and Australia, in order to understand cellular pathways regulating response or resistance in DIPG, a research paradigm that will reveal complementary treatment targets to improve outcomes.