CSIG-34. LIN28B-LET-7-PBK PATHWAY IS AN IMPORTANT REGULATOR OF GROUP 3 MEDULLOBLASTOMA PROLIFERATION

Abstract Children with Group 3 medulloblastoma (MB) have a very poor long-term outcome and many do not survive beyond 5 years. Several drivers for MB been identified but none resulted in targeted therapy to date. LIN28B is stem cell factor upregulated associated worse survival. Here we investigate the role of pathway development. Pharmacologic inhibition feasible may provide unique opportunity target this tumor. Using knockdown overexpression cells test LIN28B’s effect on proliferation, self-renewal metastasis. We survival as well proliferation apoptosis markers using orthotopic xenografts vivo. also let-7 its downstream PBK proliferation. Finally, use LIN28 inhibitor 1632 HITOPK032 treat lines then assess their impact apoptosis. find that down-regulation or shRNA results significant reduction In contrast increases tumor sphere formation. significantly (p< 0.01) mice tumors. The leads growth through decreased cycle entry increased addition, demonstrates at low micromolar concentration. demonstrate combination CDK 4/6 can additively inhibit cells. Our study establishes critical LIN28B-let-7-PBK Group3 provides encouraging preliminary preclinical drugs pathway.