HG-16: CDK7 INHIBITION IN DIFFUSE INTRINSIC PONTINE GLIOMA

BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) remains a universally fatal childhood cancer with a median survival of less than 1 year. Focal radiation remains the standard of care as no conventional chemotherapy has improved survival. The majority of DIPGs contain H3K27M mutations in histones 3.1 and 3.3, driving globally increased gene expression. Panobinostat, a histone deacetylase (HDAC) inhibitor, restores methylation at H3K27 and extends survival in DIPG xenograft models, though drug resistance develops. DIPG overexpress MYC, which is associated with super-enhancer dysregulation and increased proliferation. CDK7 inhibition blocks the phosphorylation of RNA polymerase II (Pol II). As Pol II catalyzes transcription through the preinitiation complex, its inactivation decreases gene expression. Attacking multiple pathways within DIPG may prove efficacious and combinatorial epigenetic strategies are particularly promising. OBJECTIVE: To evaluate the effect of a CDK7 inhibitor as a single agent and in combination with panobinostat in treating DIPG by using patient-derived DIPG cell cultures and xenograpft models. METHODS: Multiple DIPG cell cultures, including H3K27M and wildtype, were treated with a pharmacological CDK7 inhibitor as a single agent and with panobinostat. Cell proliferation was evaluated using Cell Titer-Blue® (Promega). RESULTS: CDK7 inhibition significantly decreases cell proliferation with an IC₅₀ of 80 nM. The effect is synergistic with panobinostat, whose IC₅₀ is 100 nM; together with only 25 nM of the CDK7 inhibitor the IC₅₀ of panobinostat decreases to 50 nM. CONCLUSION: Panobinostat is in clinical trials for DIPG, though pre-clinical models suggest drug resistance develops. This study suggests CDK7 inhibition is synergistic with HDAC inhibition in DIPG.