Abstract 4299: Validation of the antitumor compound 3797 in human and murine glioblastoma models

Abstract Multiple studies have highlighted the critical role of the RB-E2F pathway in the control of cell proliferation, therefore, decreasing E2F hyperactivity could be a valuable therapeutic strategy in cancer. Based on this, we propose a therapeutic approach in which E2F transcriptional activity is specifically reduced in cells that show hyperactivation of this pathway, in other words, tumor cells. Preliminary data obtained in the group show that poly (ADP-ribose) polymerase-1 (PARP1) is a transcriptional co-activator of E2F1 and, because of this, loss of PARP results in cell cycle regulation and reduced tumor growth. Furthermore, taking into consideration that most oncogenic processes are associated with cell cycle dysregulation, disruption of the PARP1-E2F1 interaction could provide a new therapeutic target for various tumor types. By searching for compounds that can interfere with the PARP1/E2F1 interaction, our group has obtained a library of 85 compounds generated by in silico screening of millions of commercially available compounds using a drug discovery platform. After initial in vitro screening, we have identified 12 molecules capable of inhibiting this interaction. The one that performed best was selected for validation using 2D and 3D models of human and murine glioblastoma. For this purpose, we carried out cell viability and migration assays to assess the effect of the compound on two murine and one human glioma cell lines. In all cell lines, cell growth was decreased by treatment, as revealed by violet crystal staining. In addition, wound closure response was inhibited in treated cells as compared with controls. Finally, the therapeutic efficacy of compound 3797 was tested in organoids originated from those tumor cell lines, using the lactate dehydrogenase (LDH) assay, which assess the cell metabolic activity. In keeping with results obtained in 2D cultures, LDH assay showed that compound 3797 decreases the growth rate in organoids derived from glioblastoma cell lines. This work was supported by Agencia Estatal de Investigación (AEl/10.13039/501100011033), Xunta de Galicia (GPC GI-1862, ED431B 2020/26; ED431G 2019/02) and European Regional Development Fund-ERDF. AIMS Awards Program - Project A19-513, Atomwise Inc. Citation Format: Lara Gonzalez-Rendo, David Moreiras-Alvarez, Martín Baleiron-Rodriguez, Laura Porres-Ventin, Jose A. Zumalave, María Isabel Loza-García, Víctor M. Arce, Jose A. Costoya. Validation of the antitumor compound 3797 in human and murine glioblastoma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4299.