Pre-doctoral Fellowship Grant Awarded to Erik Peterson

ONC201 is an investigational drug that has shown promising effects in preclinical models of DIPG and is currently undergoing clinical trials in patients. Despite promising early results, these tumors eventually return. Understanding how ONC201 is working in DIPG and how DIPGs develop resistance is critical to develop methods to combat tumor recurrence. My preliminary data from ONC201-treated DIPG models suggest that ONC201 disrupts how DIPGs extract energy from sugar molecules. Further, this data shows that once these processes are broken, ONC201-treated DIPG cells begin to use other sources of energy, such as the amino acid glutamine. I therefore hypothesize that resistance to ONC201 develops when DIPGs develop alternative strategies to meet their energy demands. Understanding the exact mechanism by which resistance may occur will highlight potential combination treatment strategies to increase ONC201’s effectiveness and improve patient outcomes. In this research proposal, I will seek to understand 1) how ONC201 slows DIPG cell growth by interfering with sugar metabolism and 2) to learn if blocking other fuel sources, such as glutamine, can overcome resistance to ONC201. In this proposal, I outline three aims: 1) I will determine changes in the cellular energy production machinery before and after ONC201 treatment, 2) I will determine how sugar and amino acid metabolism change following ONC201 in recurrent DIPG tumors in mice, and 3) I will use combination treatment strategies to overcome ONC201 by targeting the compensatory metabolic pathways used by DIPG cells to evade the inhibitory mechanism of action of ONC201.