Abstract 5922: Characterization of the biological effects of a quadruplex-interacting molecule in dedifferentiated liposarcoma cells

Abstract

Abstract G-rich nucleic acid sequences can assume, under physiologic conditions, non-B secondary structures called G-quadruplexes (G4). The human genome contains thousands of putative quadruplex forming sequences (PQS), of which telomeres are the most extensively studied. PQS are frequently found in the promoters of oncogenes and transcription factors rather than in tumor suppressor or housekeeping genes, indicating an evolutionary selection of these elements based on gene function and suggesting a pivotal role of G4 in the regulation of gene expression. These observations have provided the rationale to explore G4 targeting as a therapeutic approach in cancer. Several small molecules have been indeed designed and characterized as G4-ligands (G4-L), most of them showing a “multiple-target” binding modality. Dedifferentiated liposarcoma (DDLPS) is a non-lipogenic disease characterized by aggressive local growth and multifocal local recurrences and the ability to elicit distant metastases. At the molecular level, DDLPS is marked by the amplification of the 12q13-q15 chromosomal region, leading to the abnormal expression of the MDM2 oncogene. The gene has emerged as an actionable therapeutic target and, recently, PQS within its promoter have been reported to fold into G4 structures. In addition, in our previous study, we observed that pathways related to telomere maintenance are remarkably up-modulated in DDLPS. These findings open a new avenue to explore the therapeutic potential of G4-L in this malignancy. In the present study, the biological activity of a tetra-substituted naphthalene diimide (NDI) G4-L derivative (SOP1812/QN-302) has been characterized in two patient-derived DDLPS cell lines. In particular, the exposure of DDLPS cells to increasing concentrations of SOP1812 resulted in a marked cytotoxic activity in vitro, with IC50 values within the sub-micromolar range (~0.3 μM). Moreover, DDLPS cells treated with equitoxic amounts of the compound were characterized by an 80-90% inhibition of telomerase activity and a remarkable perturbation in the MDM2-p53 feedback loop, leading to a pronounced accumulation of basal and phosphorylated (S15/S46/S392) p53 protein. These effects were paralleled by a 3-4 time increase in the number of γ-H2AX foci, the appearance of the cleaved form of PARP-1 and a pronounced inhibition of cell growth over time. Altogether, our findings indicate that targeting G4 structures by quadruplex-interacting molecules may represent a potential novel and effective therapeutic strategy in DDLPS. Citation Format: Eisa Naghshineh, Beatrice Tosoni, Lorenzo Di Pietro, Sandro Pasquali, Nadia Zaffaroni, Stephen Neidle, Sara N. Richter, Marco Folini. Characterization of the biological effects of a quadruplex-interacting molecule in dedifferentiated liposarcoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5922.