CNSC-64. PYRVINIUM ATTENUATES MEDULLOBLASTOMA PROGENITOR CELL PROLIFERATION AND SELF-RENEWAL

Abstract BACKGROUND Medulloblastoma (MB) is the most common malignant pediatric brain tumor and a leading cause of cancer-related deaths in children. One-third of MB patients experience tumor recurrence with an average survival of 10 months and thereby representing a major clinical challenge. Previously, our lab identified a pool of MB progenitor cells (MPCs) facilitating relapse in a Glioma-associated oncogene (GLI)-dependent manner. Thus, blocking GLI transcriptional activity reduced relapse risk in animal models. However, implying the contributions of additional mechanisms, relapses occurred in ~50% of GLI inhibitor-treated mice. Our previous studies showed that self-renewal of Trp53 mutant MPCs was driven by WNT. Thus, we wondered whether dual GLI/WNT inhibition would have improved efficacy in P53-deficient MB. METHODS The efficacy of a GLI/WNT dual inhibitor acting on CK1a, pyrvinium, in blocking MB propagation and self-renewal was determined in MPC cultures and allografts. Gain/loss-of-function assays were performed to validate pyrvinium’s results. RESULTS According to its capacity to reduce GLI stability, pyrvinium attenuated the proliferation of MPC cultures. In line with our previous publications and unlike other GLI inhibitory strategies, pyrvinium also reduced the WNT-driven self-renewal of Trp53 mutant MPC cultures. In vivo, pyrvinium reduced MB growth while also abrogating primary and secondary tumor engraftment. Curiously, pyrvinium not only blocked MB self-renewal in Trp53 mutant MB models, but also in wild-type ones. A candidate-based approach showed that pyrvinium blocks STAT3 activation in MPC cultures regardless of their Trp53 background. Therefore, like pyrvinium, STAT3 inhibition attenuated MB self-renewal. CONCLUSION Our data uncovers STAT3’s contribution to MB self-renewal, and therefore to the relapse of these tumors. Due to its likely advantage over compounds acting on GLI or STAT3, our results also suggest the potential of repurposing the dual inhibitor pyrvinium for the treatment of MB.