SENESCENCE

Senescent cells are associated with chronic disease and cancer metastases in human and were shown to be drivers thereof in. For instance, we have shown before that interference with FOXO4-p53 through cell penetrating peptides could selectively eliminate senescent cells in mouse models where senescence is enhanced through defective DNA-damage repair (Baar .. de Keizer, Cell, 2017). Doing so could restore some signs of homeostasis. There have been many attempts towards development of compounds to eliminate senescent cells, but with varying success. At least in part, this is because of a lack of understanding of the different aspects of senescence. At the summit, I will discuss how we identified that what we call senescence, is in fact a range of phenotypes. Through multiplex characterization, we identified there is considerable heterogeneity even within the same population of senescent cells. I will provide examples and zoom a damaged type of senescence, which we call now call “scarred” senescence, a subtype characterized both by FOXO4/PML and a modified form of p53, i.e. phosphorylated on Ser46. I will show that at least for this type of senescence, we have been able to apply new structural and biomolecular insights to progressively develop potent therapeutics, i.e. compounds CL04177 and CL04183. I will now show in more detail how this may be particularly true for scarred senescent and cancer cells. From a translational point of view, I will show how human cancer cells in patients, in vitro, in 3D organoids and in vivo can present a state of scarring and thereby provide in ideal target disease for testing the efficacy of scarring-targeting FOXO4 peptides. Moreover, I will show how CL04177 potently counters metastases in vivo at dosing scheme and frequency that are well below the Maximally Tolerated Dose and applicable for preclinical translation. Together, this argues we should better define senescence subtypes and focus on specific therapeutics. Scarred senescence can especially be targeted by FOXO4-based peptides, with a translational potential to the clinic.