CSIG-31. T-TYPE CALCIUM CHANNEL BLOCKERS INDUCE METABOLIC ALTERATIONS AND APOPTOSIS IN MEDULLOBLASTOMA CELLS

Abstract Medulloblastoma (MB) is the most common malignant paediatric brain tumour. In our previous studies, in a screen of panel calcium channel modulators novel high-throughput 3D assay, we identified T-type (CaV3) inhibitors, mibefradil and NNC-55-0396 (NNC) as selective inhibitors MB cell growth. Mibefradil was originally approved for treatment hypertension angina pectoris, recently successfully completed Phase-I trial recurrent high-grade glioma. NNC an analogue with multiple advantages compared to that makes it attractive potential future clinical trials. channels have unique low voltage-dependent activation/inactivation, many studies suggest they direct regulatory role controlling Ca2+ signalling non-excitable tissues, including cancers. this study, characterized effect on cells elucidated their mechanism action. This study demonstrates induction toxicity but not L-type inhibitors. Addition CaV3 vincristine sensitised chemotherapeutic agent, suggesting additive effect. Furthermore, induced death via apoptosis. Supported by proteomics data cellular assays, apoptotic associated reduced mitochondrial membrane ATP levels, which suggests both compounds alter metabolism cells. We also CACNA1H (encoding CaV3.2 protein) significantly upregulated aggressive Groups 3 4 patient samples, its higher expression metastasis lower survival rates. offers new insights into action will pave way test these molecules or analogues pre-clinical models alone combination assess suitability therapy.