Mentor Name: Jessica Tsai

Atypical teratoid rhabdoid tumors (ATRT) are extremely aggressive childhood central nervous system tumors that most often affect children age 3 and younger. The majority of ATRT cases are characterized by bi-allelic deletions in SMARCB1, while the remaining cases harbor SMARCA4 loss of function mutations. More recent transcriptomic and epigenetic data have led to the development of ATRT molecular subgrouping; however current treatment does not distinguish between these subgroups. While there have been some improvements in clinical outcomes with multimodal therapy (including surgical resection, cytotoxic chemotherapy, radiation, and high-dose chemotherapy followed by autologous stem cell transplantation), there remains significant morbidity and toxicities associated with such intensive therapy. Treatment with cytotoxic chemotherapy as well as high dose chemotherapy can result in severe toxicities including life-threatening infections, bleeding, and organ failure, which are particularly challenging in the younger age group of children affected by ATRT. Focal radiation and craniospinal radiation can have devastating neurodevelopmental effects in children under the age of 3. Cancer cells harbor the remarkable ability to hijack cellular metabolism to facilitate tumor survival. We have found that ATRT cells exhibit high expression of ferrochelatase (FECH). FECH is the rate-limiting enzyme in heme biosynthesis that facilitates the insertion and consumption of iron into protoporphyrin to form heme. Importantly, iron is essential to ferroptosis, a novel form of iron-dependent cell death. In adult cancers, FECH inhibition is thought to result in excess iron, triggering ferroptosis. Previously, we have shown that FECH is a unique vulnerability in ATRT cells. This project will utilize Western blotting and transcriptomics to understand how FECH inhibition kills ATRT cells.