DDDR-30. Targeting wtIDH1 in radiation-resistant medulloblastoma

Medulloblastoma is molecularly characterized into 4 main subgroups consisting of WNT, SHH, Grp 3 and Grp 4, which are further divided into 13 subtypes. Medulloblastoma manifests as a clinically heterogeneous tumor with varying prognoses depending on the molecular subgroup. Treatments for high-risk patients include craniospinal irradiation (36Gy) after surgical resection and chemotherapy. Group 3 tumors with upfront radiation therapy relapse in a shorter amount of time at 1 year. Currently, there are limited therapeutic strategies that address medulloblastoma tumor recurrence which has detrimental effects on patient outcome with <5% long term survival. Subsequently, there is a critical need to investigate the molecular mechanisms underlying therapeutic resistance in medulloblastoma and identify the best strategies to combat it. To understand what causes radiation resistance in medulloblastoma, we analyzed matched primary and relapsed patient tumors by single cell ATAC seq + gene expression. We further evaluated radiation resistance in an orthotopic mouse model and analyzed gene expression changes by single-cell RNA sequencing. We identify a resistant cell population that exhibits a distinctive gene signature comprising stem and metabolic gene transcription programs. We observe elevated expression of metabolic marker genes such as wtIDH1 and stem cell markers, TEAD1 and SOX6, within the recurrent cell population. We speculate that radiation resistance in group 3 medulloblastoma is facilitated by wtIDH1 metabolic reprogramming, leading to epigenetic adaptation and cell persistence. Thus, we evaluate how IDH1 changes the epigenetic landscape of radiation-resistant and sensitive cells by examining histone modifications (H3K27ac, H3K27me3, H3K4me3) and the broader chromatin architecture in response to IDH1 inhibition by Cut and Run and ATAC-sequencing. We observe that the manipulation of wtIDH1 reduces MB cell growth, stemness characteristics, and changes the chromatin landscape. Further, we find inhibition of wtIDH1 enhances susceptibility to re-irradiation and provides a survival benefit. Our results highlight evidence of the development of radiation resistance and provide a potential therapeutic alternative for treatment of relapsed MB.