RBIO-10. Targeting telomere maintenance sensitizes group 3 medulloblastomas to ionizing radiation

Abstract Ionizing radiation (IR) is part of standard care for group 3 (G3) medulloblastomas (MBs), the most aggressive molecular subtype of the most common malignant pediatric brain cancer. However, IR is often not curative and causes debilitating neurological side effects. There is a critical need for adjuvants to make IR more effective. We screened in-house (N=57) and public (N=375) single-cell and bulk RNA and epigenetic datasets for correlates of G3 MB progenitor cell types. We identified a telomere maintenance signature driven by zinc finger and scan domain 4 (ZSCAN4) that is upregulated in cycling progenitors vs. neuronal-like G3 MB cells. ZSCAN4 positively regulates telomere elongation and genomic stability in early embryos. Our data indicate that ZSCAN4 plays a similar role in G3 MBs. In particular, we found that ZSCAN4 and its targets are upregulated in embryonal brain tumors vs. diffuse gliomas, and in recurrent G3 MBs vs. matched primary cases. ZSCAN4 positively regulated telomere lengths in G3 cell lines. CRISPR inhibition of ZSCAN4 led to significant DNA damage, telomeric DNA damage, decreased tumor proliferation, and significantly increased survival and sensitivity to IR in vivo. ZSCAN4 expression was significantly reduced, and the survival of orthotopic xenografts significantly increased, by repurposing oral FDA-approved brain-penetrant drugs, with no toxicities. Our studies indicate that an embryonal mechanism of telomere maintenance and genomic stability mediated by ZSCAN4 is utilized by embryonal brain tumors and can be targeted for therapeutic benefit.