MBRS-62. CURAXIN CBL0137 INHIBITS THE VIABILITY OF CANCEROUS CELLS IN PRE-CLINIC MODELS OF MYC-AMPLIFIED MEDULLOBLASTOMA

Abstract

Medulloblastoma is a malignant brain tumour that mostly occurs in children, and MYC-amplified medulloblastoma is characterized by pronounced invasiveness and dismal prognosis. There is no effective treatment for Medulloblastoma and its precise pathological mechanism remains obscure. Previous studies indicated that the altered epigenetic machinery manifested in the neoplastic transformation of MYC-amplified MB has become increasingly evident. It is hypothesized that epigenetic genes dependencies associated with small molecule inhibitors that have been approved or are in advanced development may help identify the potential therapeutic targets. By integrating mRNA expression profiles and the corresponding clinic-pathologic information of patients suffering from medulloblastoma, and analysing prior CRISPR screening results, we demonstrated that SSRP1 is a negative prognostic factor that functions to stimulate the viability of MB cells. SSRP1 is a subunit of the FACT complex, an important histone chaperone required for transcriptional regulation, DNA replication and damage repair. Its biological effect on tumour proliferation was assessed by using RNA interference and administering CBL0137, a small molecular inhibitor of FACT. Gene expression analysis also demonstrated that CBL0137 selectively downregulated the expression of MYC and NEUROD1. Furthermore, the administration of CBL0137 suppressed tumour growth in mouse xenograft models. This pharmacological method to selectively target MYC transcription was demonstrated in our study, and therefore can be applied as a promising treatment strategy for MYC-amplified medulloblastoma. In Conclusion, we identified an attractive strategy of selectively downregulating MYC transcription by applying inhibitor CBL0137, thereby revealing the potential clinical utility of CBL0137 to improve the prognosis of MYC-amplified medulloblastoma patients.