Targeting MBD2 for medulloblastoma therapy

The present proposal aims to develop novel small molecules for epigenetic therapy of medulloblastoma (MB) with the goal of translating them to the clinic. MB is the most common and aggressive malignant brain tumor in children. Current nonspecific cytotoxic therapies cure only a fraction of patients, and cause life-long neurological, intellectual, and physical disabilities, highlighting the urgent need for novel therapeutic approaches. ADGRB1 (BAI1) is an adhesion G protein-coupled receptor (GPCR) specifically expressed in the brain, where it functions as a tumor suppressor. We have recently shown that ADGRB1 expression is significantly reduced in patients with MBs across all 4 main molecular groups because the ADGRB1 gene promoter is epigenetically silenced through CpG island methylation. We showed the involvement of methyl CpG binding protein 2 (MBD2) in the switch to a silent chromatin conformation and demonstrated that we could reactivate the gene through a novel small molecule inhibitor of MBD2 (KCC07). This lead compound significantly extended the survival of mice carrying human MB xenografts in the cerebellum and sensitized them to radiotherapy, providing proof-of-principle for the further development of this chemotype as a new drug for patient treatment. Importantly, KCC07 had excellent brain distribution, was very well tolerated by the mice and no overt toxicity was observed. We propose to perform medicinal chemistry to further optimize this promising chemical scaffold and conduct further IND-directed preclinical studies towards identifying a candidate compound to be evaluated in clinical trials. The proposed study has the potential to generate a new epigenetic therapeutic for children suffering from this disease and improve their survival with reduced side effects. Project Number: 1R01NS144449-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: ERWIN VAN MEIR | Institution: UNIVERSITY OF ALABAMA AT BIRMINGHAM, BIRMINGHAM, AL | Award Amount: $564,045 | Activity Code: R01 | Study Section: Advancing Therapeutics A Study Section [ATA] View on NIH RePORTER: https://reporter.nih.gov/project-details/11205828