Napolitano, Fabiana (2023) G-Quadruplex binders and dl922-947: a potential novel treatment against breast cancer. [Tesi di dottorato]

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Breast cancer is the most common female malignancy and is the second cause of cancer-related deaths in women. Although most anticancer therapies block tumor growth, in most cases, their effect is not long-lasting and their failure affects patient survival. Thus, novel therapeutic approaches are needed. Oncolytic viruses represent a novel therapeutic tool for the treatment of aggressive tumors. Oncolytic viruses selectively replicate in and kill cancer cells. Oncolytic viruses have demonstrated limited efficacy in the clinical setting as single agents, while novel combinatorial therapies showed improved clinical outcomes. This study represents the first approach combining the oncolytic adenovirus dl922-947 and G4 ligands, BRACO-19 and Pyridostatin in breast cancer cells. G-quadruplexes are non-canonical secondary structures folded by guanine (G)-rich sequences in nucleic acids, detected at telomeres and oncogenic promoters. G-quadruplexes stabilization represents a potential anticancer strategy resulting in obstruction of DNA replication impairment, induction of DNA damage and suppression of oncogene transcription, which consequently restrain cancer cell development and survival. We demonstrated that G-quadruplexes binders induce cytotoxicity in a panel of cancer cell lines deriving from breast cancer, anaplastic thyroid carcinoma and prostate cancer. The lower IC50 concentration was obtained in breast cancer cell lines that were then selected for further studies. In these cell lines we also demonstrated a cytotoxic effect of dl922-947. In MCF-7 cells, both BRACO-19 and Pyridostatin stabilize G-quadruplexes motifs, while in MDA-MB-231 cells only pyridostatin was able to stabilize G4 motifs. Pyridostatin/dl922-947 combination increased cell cytotoxicity in both cell lines, while BRACO.-19/dl922-947 combination did not modify significantly cell survival compared to the single agents, however, both combinations affected cell cycle progression. Interestingly, we demonstrated that G-quadruplexes ligands increased viral entry and replication. Notably, dl922-947 induces G-quadruplexes motifs and its combination with Pyridostatin potentiates this effect in MCF-7 cells. The agents alone or in combination similarly increased cell senescence. Additionally, Pyridostatin/dl922-947 combination inactivated STING signalling in MDA-MB-231 cells. Our results suggest that the combination of the oncolytic adenovirus dl922-947 with G-quadruplexes ligands could represent a novel and effective therapeutic approach for the treatment of breast cancer.

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