Introduction: Ovarian cancer (OC) is amongst the most lethal cancers in Canada. High-grade serous ovarian cancer (HGSC) usually responds to initial therapy, however resistance to drugs often develops over time. We have described a new two-step OC combo-therapy: 1st, a PARP inhibitor is used to induce a senescence proliferation arrest in cancer cells followed by, 2nd, the induction of senolysis in senescent cancer cells using the Bcl-2 family inhibitor ABT263, which redirects senescent cells towards apoptosis.

Our hypothesis is that therapy-induced senescence (TIS) could be beneficial in the clinic, but questions remain on its exact function in this context. Our objective is to characterise the spatiotemporal evolution of senescence during OC treatment using xenograft mouse models to define the senescence peak in tissues and optimize the targeting of senolysis approaches.

Methods-results: We generate a tumor biobank consisting of OV1946, OV4453 and MDAMB231 preclinical xenograft models treated with combinations of the PARP inhibitor Olaparib and ABT263. In all models, PARPi-ABT263 resulted in a significant reduction in tumour growth compared to each drug alone. To explore spatiotemporal cell fate decisions including senescence, a time course analysis was performed by gene expression analysis, SA-βgal staining and COMET multiplexing. COMET is an immunofluorescence technology that allows up to 40 molecular biomarkers (vasculature, epithelium, senescence phenotypes, DNA damage response) at single-cell resolution on paraffin embedded tumours.

Conclusion: We propose that characterising the cell fate decisions within the tumour including senescence can be used to improve drug administration patterns in combo therapies and reduce resistance. For example, this should refine targets and timing to improve chemotherapies that aim to manipulate senescence.