Abstract 2235: A treatment for glioblastoma with a novel epigenetic inhibitor and identification of its target

Abstract

Abstract Glioblastoma multiforme (GBM) is one of the deadliest human cancers. Despite extensive efforts to develop a new treatment, the prognoses of patients have not changed dramatically over the past several decades. LSD1 plays an essential role in the epigenetic regulation of gene expression in many cancer cells, including GBM, as it removes methyl groups from histone H3 lysine (K) 4me1/2 and H3K9me1/2. Since it was reported that suppression of LSD1 induced apoptosis of glioblastoma stem cells (GSCs), LSD1 has been expected as an effective therapeutic target for GBMs, particularly enriched with GSCs. We newly discovered an LSD inhibitor (S2172) that suppressed the LSD1 enzymatic activity effectively and sufficiently penetrated into brain. We found that S2172 showed a strong inhibitory effect on cell growth not only in GCS cells but also in differentiated GBM cells in vitro. In GBM cell line U251, IC50 of S2172 was lower than that of other LSD1 inhibitors (IC50 10.5 μM, 29.5 μM, 11.0 μM treated with S2172, Ory-1001, and CC-90011, respectively). We also found a robust suppression of transcription of oncogene Myc in differentiated GBM cells after S2172 treatment, which is highly expressed in most GBM cells and considered as a key element to maintain its stemness and proliferation. Consistent with the expression analysis, chromatin immunoprecipitation-sequencing (ChIP-seq) revealed that enrichment of H3K4m2 and H3K4m3 was efficiently altered by S2172 treatment along with the change of Myc expression. Finally, we treated U251 brain tumor mouse model with S2172. While S2172 had a strong effect in vitro, S2172 seemed unsuccessful in killing differentiated GBM cells in vivo. These data suggests that treatment of S2172 is less effective to differentiated GBM cells and this is consistent with previous report that LSD1 as a candidate therapeutic target in stem-like tumor propagating cells in GBM. Citation Format: Tokunaga Kota. A treatment for glioblastoma with a novel epigenetic inhibitor and identification of its target [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2235.