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Lienard Schmitz: Synthetic lethal targeting of metabolic pathways in ovarian cancer

AIM: The NF-κB-driven SASP has both anti- and pro-tumorigenic potential and impacts therapy responses. We have previously found that simultaneous interference with glycolysis and oxidative phosphorylation by double treatment with (R)-GNE-140 and BMS-986205 leads to the induction of senescence in fallopian tube-derived ovarian cancer cells, while immortalized fallopian tube cells remained largely unaffected. Based on these findings we will explore the effects of (R)-GNE-140/BMS-986205 treatment on tumor cell-intrinsic pathways and the tumor cell-extrinsic secretome. We will also investigate the impact of the secretome from treated tumor cells on non-malignant cells within the tumor microenvironment, with a particular emphasis on immune cells.

STATE of the ART: Malignant cells exhibit metabolic changes, when compared to their normal counterparts, owing to both genetic and epigenetic alterations. These metabolic alterations are used for diagnosis such as PET scans, but also offer new therapeutic options. One effect of metabolic inhibition can be the induction of apoptosis or senescence in the tumor cells. Though they no longer divide, senescent cells remain metabolically active and secrete a plethora of proteins to mediate both anti- and pro-tumorigenic effects. To block the tumor-promoting effects of senescence, senotherapeutic approaches have been developed and have started to deliver promising results. While agents termed senolytics selectively kill senescent tumor cells, senomorphic drugs lead to reduced production and secretion of SASP factors.