THER-31. TARGETING THE HISTONE DEMETHYLASE LSD1 FOR SELECTIVE APOPTOSIS AND IMMUNE-SENSITIZATION IN PEDIATRIC DIPG

Abstract

Pediatric midline gliomas, mainly DIPGs, are a rare and deadly cancer of early childhood, with a 9-month median survival post-diagnosis and a 2-year survival rate of <10%. Their growth on the brainstem makes surgical resection nearly impossible and radiation is primarily palliative. Epigenetic therapies have shown pre-clinical promise in patient-derived DIPG models, however the H3K4 demethylase LSD1 remains an unexplored target in this disease. Clinical trials of LSD1 inhibitors (LSD1i) are currently underway in AML, Ewing’s sarcoma, lung, and prostate cancers. In our studies, treatment with LSD1 inhibitors tranylcypromine (TCP) (IC₅₀: ~1.5mM), GSK LSD1 (IC₅₀: ~400uM), RN-1 (IC₅₀: ~60uM), and SP-2509 or its clinical successor Seclidemstat (SP-2577) (IC₅₀: ~13uM) is selectively cytotoxic to DIPG cells over normal human astrocytes (NHA). Cellular thermal shift assay (CETSA) confirms target engagement of TCP-derived LSD1 inhibitors in DIPG cells at therapeutically relevant doses. Epigenetic therapies can also change the transcriptome of cells, so we mined our previously published RNA-Seq data for potential combination therapy approaches with LSD1 inhibitors. Pathway analysis revealed immune response genes to be significantly changed by LSD1 knockdown. Sub-cytotoxic LSD1i treatment can replicate these changes in DIPG cells but not normal human astrocytes. Pre-treatment of DIPG enhances lysis by NK cells but not T-cells, and the novel genes LCP1/IL18/LAT2 are highly correlated with increasing NK lysis. Using a clustering algorithm in a dataset of 247 pediatric high-grade gliomas, a 13-gene upregulation signature correlates with increased survival and inversely correlates with LSD1 expression (p = 0.0087, unpaired T-test). Immunocompetent murine models of DIPG that possess the H3-K27M mutation and display highly similar LSD1i sensitivity to human DIPG in vitroare currently being dosed in vivo. Our findings support that LSD1 can be targeted in DIPG for both direct cytotoxicity and as a transcriptional modifier in combination with immunotherapy regimens.