Abstract 2730: Antisense-oligonucleotide therapy targeting BRAF alleviates pediatric brain tumors with intractable epilepsy

Field: Medicine (Health Sciences)

Abstract Rationale: BRAF mutations leading to aberrant MAPK/ERK signaling are one of the major driver mutations in low-grade pediatric brain tumors (e.g., pilocytic astrocytoma, ganglioglioma, dysembryoplastic neuroepithelial tumor, and diffuse astrocytoma). These variants are highly associated with poor prognosis and intractable epilepsy. We previously identified that BRAF mutations originate from neural stem cells during embryonic brain development and lead to epilepsy-associated pediatric brain tumors (Koh et al, Nat Med 2018). Existing BRAF inhibitors such as Vemurafenib and Dabrafenib are specific to BRAF V600E protein and have limited penetrance into the blood-brain barrier (BBB). Antisense oligonucleotide (ASO) therapy via intrathecal injection bypasses BBB and degrades the transcript of the target gene in the brain. Thus, it is a promising and effective therapeutic tool in neurological disorders with genetically and molecularly identified targets. Methods: We developed the genetically engineered mouse model of Braf-derived pediatric brain tumors with intractable epilepsy by introducing Braf p.V600E mutation into neural stem cells during embryonic brain development. These mice show a gradual increase in tumor size and epileptic seizures and a decrease in survival rate over time, thereby recapitulating BRAF-derived pediatric brain tumors with intractable epilepsy. We administrated the most effective ASO inhibiting mouse Braf RNA selected by in silico and in vitro screening. ASO was delivered by single bolus intracerebroventricular (i.c.v.) injection at 10 weeks after pre-monitoring of behavior seizure and tumor size. Results: Oral administration of existing BRAF inhibitors could not significantly reduce seizures and tumor size in BRAF pediatric tumor models. Single ICV injection of Braf ASO successfully reduced the transcript and encoded protein in a dose-dependent manner and its knock-down effect lasted at least 3 months. Injected ASOs are well distributed to CD34-positive regions and tumor cells in Braf-derived neuro-glial tumors. The behavioral and electrographic seizure frequency is remarkably reduced after treatment of the ASO. The size of tumors and enlarged dysmorphic neurons are significantly reduced. The survival rate was significantly increased. Also, the bodyweight is rescued in Braf ASO treated group, compared to the vehicle-treated control group. No behavioral and molecular toxicity was found at two months after i.c.v. administration of ASO. Conclusions: In our study, ASO therapy targeting BRAF shows strong therapeutic effects on various aspects of BRAF-derived pediatric brain tumors, including the epileptic seizures, tumor size, survival rate as well as dysmorphic neurons. Therefore, ASO therapy targeting BRAF will be a promising and effect therapy in BRAF-derived pediatric brain tumors with intractable epilepsy. Citation Format: Jeong Ho Lee, Seyeon Kim. Antisense-oligonucleotide therapy targeting BRAF alleviates pediatric brain tumors with intractable epilepsy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2730.