Targeting CDK7 or BRD4 Blocks Diffuse Intrinsic Pontine Glioma Growth

The large majority of diffuse intrinsic pontine gliomas (DIPG) harbor a mutation in histone H3 (H3K27M) that drives oncogenic transcription. Targeting aberrant transcription with the histone deacetylase (HDAC) inhibitor panobinostat has had some success in preclinical and early clinical studies. However, resistance to HDAC inhibition eventually develops, and alternative therapies to disrupt oncogenic gene expression are needed to treat patients with DIPG. Nagaraja and colleagues investigated the use of bromodomain and extra-terminal domain (BET) inhibitors and CDK7 inhibitors to block oncogenic transcription. The BET inhibitor JQ1 suppressed the growth of patient-derived H3K27M DIPG cells, but BET inhibitors in clinical development had insufficient brain penetration and potency for in vivo use. Nevertheless, BRD4 depletion in DIPG orthotopic xenografts resulted in reduced tumor growth and improved survival, indicating that BRD4 may be a therapeutic target when appropriate pharmacological agents are developed. Similarly, the CDK7 inhibitor THZ1 impaired the growth of H3K27M DIPG cells in vitro, and reduced tumor burden and extended survival in patient-derived DIPG xenograft models. Further, JQ1 and THZ1 synergized with HDAC inhibition to suppress DIPG cell growth, suggesting the possibility for dual targeting. Cells resistant to panobinostat retained sensitivity to THZ1, but not JQ1, suggesting that panobinostat and THZ1 have dissimilar mechanisms of action. Consistent with these findings, panobinostat and JQ1 downregulated a largely overlapping set of target genes, whereas THZ1 disrupted expression of distinct target genes. Characterization of the superenhancer landscape in DIPG cells found that many of the super-enhancer-associated genes were characteristic of oligodendrocyte precursor cells, suggesting that the DIPG cell of origin may be an early oligodendroglial precursor cell. Treatment with panobinostat and THZ1 disrupted expression of these DIPG superenhancer-associated genes to block oncogenic transcription. In addition to discovering the potential DIPG cell of origin, these findings suggest that targeting CDK7 or BRD4 may synergize with HDAC inhibition to suppress DIPG.

Nagaraja S, Vitanza NA, Woo PJ, Taylor KR, Liu F, Zhang L, et al. Transcriptional dependencies in diffuse intrinsic pontine glioma. Cancer Cell 2017 Apr 20 [Epub ahead of print].