Castellano, Giuliano (2025) Novel Therapeutic Approaches for Triple Negative Breast Cancer (TNBC). [Tesi di dottorato]

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Abstract

Triple negative breast cancer (TNBC) is a subtype of breast cancer (BC) lacking estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2/neu+ or ERBB2+). It is associated with high invasiveness, poor prognosis, tendency to relapse and metastasis formation in distant site, such as lung, brain and bones. Currently, the therapeutic approach for BC treatment is mainly based on molecular targeted therapy and despite some steps forward, the lack of hormonal receptors in TNBC subtype makes the treatment extremely challenging. TNBC is commonly treated with neoadjuvant chemotherapies (NACT), however, most of the patients often go through frequent relapses and metastatic progression. Novel therapeutic approaches are urgently needed. Among them, oncolytic viruses (OVs) and G-quadruplex (G4) stabilization by G4 ligands represent a highly promising research field. The research activities carried out during my PhD concerned the anticancer effect of the oncolytic adenovirus dl922-947 in TNBC cell lines. We demonstrated a cytotoxic effect of this virus in MDA-MB-231 and MDA-MB-468 cells, induction of apoptosis and immunogenic cell death (ICD), characterized by the modulation of three main damage-associated molecular pattern (DAMPs): cell surface calreticulin (CALR) exposure, adenosine triphosphate (ATP) and high-mobility group box 1 (HMGB1) release. It also reduced the secretion of the pro- tumorigenic cytokine IL-6. Studies suggest an increased effect of virotherapy in combination with other anti-cancer treatments. In this context, we investigated the combination of the virus with G4 ligands able to stabilize these motifs, thus inhibiting the transcription of genes involved in cancer growth and progression. The G4 binders BRACO19 (B19) and Pyridostatin (PDS), showed G4 stabilizing effect in BC cell lines. PDS efficiently stabilized G4 motifs in MDA-MB-231 cells. We investigated the anti- cancer effects of dl922-947 in combination with B19 and PDS, showing increased cytotoxicity using PDS consistent with enhanced viral replication in the presence of PDS. Lastly, PDS/dl922-947 combination inhibited Stimulator of Interferon Genes (STING)/STAT3 signalling pathway in MDA-MB-231 cells and increased the phagocytic rate of THP-1 cells, a cell line extensively used to study monocyte/macrophage functions. These results suggest that dl922-947 and G4 ligands might represent a promising therapeutic approach to TNBC treatment, especially when used in combination. However, further studies are needed to better characterize the potential of this combination and its specific mechanisms of action.

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