Abstract PO-003: Bivalent histone modifications: Clinical targets against pancreatic cancer stem cell heterogeneity

Bivalent histone modifications, the pre-transcriptional regulators were known as the chief orchestra underlining the mechanism of development for pancreatic cancer stem cells (PANCSCs) recently. The histone bivalency methylations are related to the transcriptional activation as well as repression of the prominent histone methylations (H3K4me3 and H3K27me3) at the transcript start sequence (TSS). These epigenetic changes are recognized to initiate heterogenic cancer stem cells (CSCs) reprogramming. Recent studies showed that the heterogenic CSCs are more resistant to anti-tumor drug therapy. Our previous study showed the relationship between bivalent histone modifications with the expression of pancreatic CSCs(CD44, CD24, CD133, Ep-CAM, ALDH1A3). Our current study is focused on the importance of designing anti-cancer drugs or epigenetic small molecules against bivalent histone modifications (to inhibit the upregulation of H3K4me3 or down-regulation of H3K27me3) related the expression of heterogenic pancreatic CSCs (CD44, CD24, CD133, Ep-CAM, ALDH1A3). The Cancer Stem Cells Therapeutic Target Database Version 2.0 (CSCTTv2.0) reported the high CD133 as PAN CSCs and high CD133, CD44 showed resistance to anticancer drugs (such as docetaxel, 5-FU, irinotecan, oxaliplatin) in many cancers. The Gemcitabine, a nucleoside analog, and Metformin are only drugs used for pancreatic cancer treatment and showed resistance against heterogenic PANCSCs. The biological informatics analyses (Cytoscape database, HPIDb, Spike, BioGrid, Reactome, MBInfo) were deployed in our study to find the effect of bivalent histone modifications on the TSS of the target genes in heterogenic PANCSCs and we found the effect at TSS of target genes CD44, and EZH2/ENX1. We also found a novel small molecule KY-02111 has an effect to reduce the expression of heterogenic PANCSCs at tumorigenic in vitro 3D spheroids model of PANC-1ORGR (Gemcitabine resistant) cells. Therefore, our preliminary study may give an important clue to find further the role of KY-02111 against the heterogenic pancreatic CSCs by inhibiting the upregulation of H3K4me3 or down-regulation of H3K27me3 as a clinical target for pancreatic cancer therapy. Citation Format: Madhumita Das, Mayur Doke, Edwin Gonzalez, Daima Diaz, Bryan Pineda, Jonathan Celli, Marco Ruiz, Jayanta K. Das. Bivalent histone modifications: Clinical targets against pancreatic cancer stem cell heterogeneity [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-003.