Mentor Name: Bo Qiu

This project takes a precision medicine-based approach to treat ZFTA::RELA driven supratentorial ependymoma with high-risk molecular features. 1q gain is a negative prognostic feature in multiple pediatric malignancies, and recent work has demonstrated that 1q gain drives sensitivity to 5FU in posterior fossa A (PFA) ependymoma. These findings inform the development of an upcoming Children’s Oncology Group trial that will employ 5-FU therapy in newly diagnosed PFA ependymoma with 1q gain. However, it is unclear if this vulnerability is generalizable across other pediatric cancers, including supratentorial ependymoma – where patients with ZFTA::RELA fusion and 1q gain cannot be cured with contemporary therapies. Using primary patient ZFTA::RELA cell lines that have been annotated for 1q gain in our lab and the UCSF Brain Tumor Research Center, Daniel will determine if 5-FU cytotoxicity correlates with 1q gain status. We anticipate the output of Daniel’s summer project will 1) provide preliminary data on the potential application of 5-FU in supratentorial ependymoma and 2) form the foundation for ongoing studies into the determinants of 5-FU cytotoxicity in ependymoma. CDKN2A/2B deep deletion drives high-risk, treatment resistant disease in supratentorial ependymoma. CDKN2A/2B deep deletion in tumor cells is frequently associated with loss of a neighboring gene called MTAP. This leads to the accumulation of a metabolite called MTA specifically in MTAP deficient cancer, where MTA binds to the endogenous protein arginine methyltransferase PRMT5. Multiple PRMT5 inhibitors that interact selectively to MTA-bound PRMT5 (MTA-cooperative PRMT5 inhibitors) are under clinical development, including agents with blood brain barrier penetration. However, no trials are active in pediatric patients. Using the patient derived cell lines that have been clinically annotated for CDKN2A/2B deletion, Daniel will perform western blotting to determine if these lines have lost MTAP expression. He will then test MTA-cooperative PRMT5 inhibitors for cytotoxicity and PRMT5 target engagement. To solidify the concept of “therapeutic window”, we will determine if MTAP deficiency is correlated with PRMT5 target engagement and cytotoxicity.