HGG-24. PRECLINICAL EFFICACY OF THE BRAIN PENETRANT CYCLIN-DEPENDENT KINASE INHIBITOR ZOTIRACICLIB IN PEDIATRIC DIFFUSE MIDLINE GLIOMAS

Abstract

Children diagnosed with diffuse midline gliomas (DMG), including diffuse intrinsic pontine glioma (DIPG), have extremely poor outcomes with a median overall survival of 9–12 months from initial diagnosis. Standard-of-care is limited to focal radiation therapy, given the paucity of effective targeted therapies for DMG. To identify effective drugs for treatment of children diagnosed with DMG, we investigated the brain-penetrating multi cyclin-dependent kinase inhibitor Zotiraciclib (ZTR/TG02). ZTR has demonstrated encouraging response rates and a benign safety profile in phase 1 trials of adults with high-grade glioma. It is thought to achieve its anti-cancer activity mainly by transcription disruption, a previously described vulnerability of DMGs, by inhibiting multiple cyclin-dependent kinases 9 and 7 (CDK9, 7). We found that ZTR robustly reduces viability of different patient derived DMG cells in a dose-dependent manner, with a median IC50 of 201 nM across eight tested cell lines (range 11–1258 nM, 72 hrs). Consistently, we observed loss of RNA polymerase II phosphorylation after 24 hours of treatment, indicating effective CDK9 inhibition at low drug concentrations and after short incubation time. This effect was followed by depletion of short-lived proteins including MYC and the anti-apoptotic factor MCL-1. Putative biomarkers of response and resistance were identified in silico using DepMap data analysis. To assess the safety profile of ZTR, we exposed our zebrafish model to various drug concentrations and found the drug to be safe at IC50 molarity. Ongoing in vitro and in vivo studies evaluating the efficacy of ZTR in combination with promising combination therapies for more effective treatment of children with DMG are also underway.