Abstract 3904: The novel combination of PAC-1 and ONC201 circumvent H3K27M-driven pro-survival gene expression to induce DIPG cell death

Autor: Michael A. Koldobskiy, Jeffery Rubens, Antje Arnold, Ashlyn Parkhurst, Youngran Park, Eric H. Raabe, Charles G. Eberhart
Rok vydání: 2020
Předmět:
Zdroj: Cancer Research. 80:3904-3904
ISSN: 1538-7445
0008-5472
DOI: 10.1158/1538-7445.am2020-3904
Popis: Diffuse Intrinsic Pontine Gliomas (DIPGs) are universally fatal tumors, resistant to the cytotoxic effects of all known therapies. We aim to better understand the mechanisms contributing to this resistance to design new combination therapies that will improve DIPG survival. DIPG's aggressive phenotype is driven by the H3K27M oncohistone mutation that leads to global genomic DNA hypomethylation and abnormal gene expression. To identify patterns of gene expression driven by the H3K27M mutation, we introduced the H3K27M mutation into murine neural stem cells and performed whole genome bisulfite sequencing (WGBS) to evaluate for genes with the greatest differential methylation in their promoter region. These studies identified an abundance of pro-survival genes such a BCL-2, BCL-xL, MCL-1, Caspase-3, and XIAP. Western blot confirmed elevated expression of these pro-survival factors and RNA-Seq of primary human DIPG confirmed increased expression compared to normal brain. PAC-1 is a compound that cleaves protective zinc bonds to activate procaspase-3, directly inducing cell death. ONC201 is a small molecule that inhibits the anti-apoptotic protein XIAP, which prevents activated caspase-3 from translocating to the nucleus to induce apoptosis. We hypothesized that PAC-1 combined with ONC201 will circumvent these protective abnormalities in the DIPG apoptotic signaling cascade to induce tumor cell death. PAC-1 induces high rates of apoptosis in DIPG (25µM concentrations increases the percent of cells undergoing apoptosis; cleaved caspase 3 immunofluorescence assay 5% to 30% (t-test p40% compared to DMSO control (ANOVA p Citation Format: Ashlyn Parkhurst, Youngran Park, Antje Arnold, Michael Koldobskiy, Charles Eberhart, Eric Raabe, Jeffery Rubens. The novel combination of PAC-1 and ONC201 circumvent H3K27M-driven pro-survival gene expression to induce DIPG cell death [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3904.
Databáze: OpenAIRE
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