Project Details

RNA-based Antisense Oligonucleotide Strategy Targeting Fusion Oncogenes in Pediatric Brain Cancer

Monica Pomaville, MD

Summary

BACKGROUND: In contrast to adult cancers that harbor recurrent genomic mutations, a defining feature of childhood cancers is the presence of oncogenic fusion proteins. An estimated 38% of all pediatric cancers carry a fusion. Many of these fusions drive tumor growth and predict outcome. GAP: In this study, I propose to directly target the ZFTA-RELA fusion in ependymoma, a pediatric brain tumor. There are no targeted treatments for patients with this disease. HYPOTHESIS: I hypothesize that using gapmer antisense oligonucleotides (ASOs) will specifically target the ZFTA-RELA fusion to induce ependymoma cell death. Furthermore, I hypothesize that direct intracranial delivery of ASOs will not induce significant toxicity in mice. METHODS: In this study, I will design ASOs that bind directly to the junction of fusion RNA. I will test these constructs in cell line and organoid models of ependymoma for their ability to induce fusion transcript knockdown, induction of apoptosis, and inhibition of downstream signaling pathways. Next, I will determine the toxicity profiles of these ASOs injected directly into the central nervous system of mice. RESULTS: Pending. IMPACT: Overall, this project pioneers the use of highly specific ASOs to target fusion junctions unique to cancer cells but not present in normal cells and will generate a clinical-grade therapy construct that can be directly translated into clinical trials. This unique strategy can be applied to other fusion-driven pediatric cancers where no targeted treatment strategies exist.