Suppressing recurrence in Sonic Hedgehog subgroup medulloblastoma using the OLIG2 inhibitor CT-179
Yuchen Li, Chaemin Lim, Taylor Dismuke, Daniel Malawsky, Sho Oasa, Zara C. Bruce, Carolin Offenhäuser, Ulrich Baumgartner, Rochelle C. J. D’Souza, Stacey L. Edwards, Juliet D. French, Lucy S. H. Ock, Sneha Nair, Haran Sivakumaran, Lachlan Harris, Andrey P. Tikunov, Duhyeong Hwang, Coral del Mar Alicea Pauneto, Mellissa Maybury, Tim Hassall, Brandon J. Wainwright, Santosh Kesari, Gregory Stein, Michael Piper, Terrance G. Johns, Marina Sokolsky‐Papkov, Lars Terenius, Vladana Vukojević, Leon McSwain, Timothy R. Gershon, Bryan W. Day
Abstract
OLIG2-expressing tumor stem cells have been shown to drive recurrence in Sonic Hedgehog (SHH)-subgroup medulloblastoma (MB) and patients urgently need specific therapies to target this tumor cell population. Here, we investigate the therapeutic potential of the brain-penetrant orally bioavailable, OLIG2 inhibitor CT-179, using SHH-MB explant organoids, PDX and GEM SHH-MB models. We find that CT-179 disrupts OLIG2 dimerization, phosphorylation and DNA binding and alters tumor cell-cycle kinetics, increasing differentiation and apoptosis. CT-179 prolongs survival in SHH-MB PDX and GEM models and potentiates radiotherapy (RT) in vivo. Single cell transcriptomic studies (scRNA-seq) confirm that CT-179 increases differentiation and implicate Cdk4 up-regulation in maintaining proliferation during treatment. Consistent with CDK4 mediating CT-179 resistance, CT-179 combines effectively with the CDK4/6 inhibitor palbociclib, further prolonging survival in vivo. These data support therapeutic targeting of OLIG2+ tumor stem cells in regimens for SHH-driven MB, to improve response, delay recurrence and ultimately improve MB patient outcomes. Previously, OLIG2-expressing stems cells have been identified as having a role in medulloblastoma recurrence. Here, the authors investigate the effects of targeting this OLIG2+ stem cell population in Sonic Hedgehog (SHH) medulloblastoma using CT-179, an OLIG2 inhibitor.