Developing Combination Therapies for Pediatric Brain Tumors to Co-target Histone Deacetylases (HDACs) and Lysine Specific Demethylase 1 (LSD1)
During Dr. Anastas, Jamie's postdoc training she generated data showing that a novel, dual LSD1/HDAC inhibitor called Corin reduces the growth of H3K27M mutant DIPG tumors (Anastas et al, Cancer Cell, 2019). One of the lab’s main goals will be to follow up on this work to optimize combinations of LSD1 and HDAC inhibitors already available for immediate clinical use in immunocompetent mouse models of pediatric brain tumors. The initial stages of the project will involve testing LSD1/HDAC inhibitor combinations against a panel of brain tumor models to assess which tumor subtypes are responsive. Based on previous data suggesting that co-targeting LSD1 and HDACs induces a neuronal-like phenotype in glioma cells, a second component of the project will be to determine the effects of these drugs on chromatin regulation in stem-like brain tumor cells versus more differentiated tumor sub-populations.
Investigating RNAPII Transcriptional Elongation in DIPG
Cancer cells require high levels of RNAPII-dependent transcription to sustain their rapid growth, which is induced, in part, by chromatin dysregulation. We have identified components of the transcription elongation machinery including, Elongin B (ELOB) in chromatin-focused CRISPR screens for pathways driving H3K27M mutant diffuse intrinsic pontine glioma (DIPG) growth. Follow-up studies confirm that knockout of ELOB reduces the growth of DIPG xenografts and that ELOB is overexpressed in tumors compared to normal brain, suggesting that ELOB is a driver of DIPG tumorigenesis. Ongoing studies are focused on understanding how specific regulators of the RNAPII transcriptional machinery, like ELOB affect H3K27M-dependent chromatin dysregulation, and at determining how aberrant activity of transcriptional regulators promotes DIPG tumorigenesis and progression.
Identification of Molecular Signatures of pHGG Drug Resistance
Targeted inhibitors like the HDAC inhibitor, panobinostat and the ClpP/DRD2-targeting drug, ONC201 are currently in clinical trials for pediatric high grade glioma (pHGG), yet their efficacy is not yet know. Very little is known about the activity of chromatin regulatory pathways in pHGG cells that are either inherently insensitive to various drugs, or in pHGG that have developed resistance to chronic drug treatment. Additional studies in the lab will be aimed at identifying epigenetic markers and functional drivers of drug resistance in pHGG and applying this knowledge towards the development of novel combination therapies.
