DIPG-21. EVALUATING THERAPEUTIC VULNERABILITIES IN DIPG USING AURORA KINASE INHIBITOR AS A NOVEL THERAPY

摘要

DIPG is one of the most aggressive pediatric brain tumors with no effective therapies. Majority of the midline high-grade pediatric gliomas carry somatic mutations of histone H3 resulting in the replacement of lysine 27 by methionine (K27M) and global loss of trimethylation on H3K27. In an effort to identify drugs for rapid clinical translation, we performed a rigorous high-throughput in vitro drug screen of FDA approved chemotherapeutics and epigenetic regulators. We have identified several major classes of drugs that potently reduce cell viability and proliferation of H3K37M tumors including the aurora kinase inhibitors (AKI). Using large cohorts from published data sets, we also confirmed a very distinct differential expression of Aurora Kinase (AK)-related genes in DIPG patients compared to normal brain and these results extended to our patient-derived H3K27M cell lines. Alisertib is a brain penetrant AKI that is orally available, with good safety and tolerability profile in children which will allow for rapid translation to the clinic. Importantly, gene expression of twelve AK related genes that we identified in our H3K27M cell lines correlated directly with sensitivity of that cell line to alisertib. We also identified an epigenetic mechanism of H3K27M trimethylation reprogramming with AKI treatment in H3K27M tumors. Finally we validated alisertib as a therapeutic target in animal models. The summation of these results supports the hypothesis that Aurora Kinases are critical for epigenetic reprogramming in H3K27M tumor cells and represents a targeted approach for treating tumors with this mutation.