New Investigator Grant Awarded to James Stafford

Diffuse intrinsic pontine glioma are a class of largely pediatric brain tumors with dismal prognosis. Resection is ineffective, they are resistance to radiation/chemotherapy and no effective treatments have been reported to date. An emerging literature suggests that the drug ONC201 is well tolerated and may have some clinical impact in discrete DIPG patient populations with current clinical trials ongoing. Our studies build on this, indicating that patient-derived DIPG cell lines exhibit high sensitivity to ONC201, dovetailing with promising survival milestones in select DIPG patients who have been placed on ONC201. However, the molecular vulnerability which ONC201 targets in DIPG has remained elusive as have other critical insights required for fully elucidating the potential of ONC201. Therefore, this proposal aims to fill that void through three complementary objectives. First, we build on preliminary data to determine if mitochondrial protease activity is the vulnerability targeted by ONC201 in DIPG. Second, we combine ONC201 with both established and novel targeting of epigenetic vulnerabilities in DIPG to determine if this combined approach might bolster its efficacy. Third, we examine the long term effects of ONC201 on tumor progression and cognitive outcomes in preclinical DIPG models, an important consideration for long-term quality of life especially in pediatric populations. Ultimately, this proposal aims to illuminate a novel vulnerability in DIPG, tractable ways to enhance its targeting and to better understand the long-term preclinical consequences of targeting that vulnerability. In doing so, we hope to reveal strategies ways to improve diagnosis and treatment of this devastating disease.