Background and Purpose: Drug repurposing has potential to improve the care for treatment resistant high-grade serous ovarian cancer (HGSOC). We hypothesised that broadly targeting PARP for drug repurposing would elicit cytotoxic responses in HGSOC through multiple biological processes. Experimental Approach: in-silico ligand-based virtual screening BLAZE was used to identify drugs with potential PARP-binding activity. The list was refined by dosing and known cytotoxicity, lipophilicity, teratogenicity, and side effects. The highest ranked drug, efavirenz, progressed to in vitro testing. Eight HGSOC cell lines were used to determine the IC50 for efavirenz. To determine the cytotoxic effects of efavirenz in a more physiologically relevant model, 3D hydrogel-encapsulated models of HGSOC and patient-derived organoid models of HGSOC were established. Live-cell imaging was employed to quantify apoptosis and cell death. Western blots, cell cycle analysis and PARP activity assays were performed to determine whether PARP1 enzyme expression and activity was inhibited following efavirenz treatment. Key Results: IC50 for efavirenz was 25.02-46.28µM for cells grown in 2D. After 7 days, IC50 doses of efavirenz reduced cell confluency and induced cell death and apoptosis. IC50 values for efavirenz in 3D models were higher ranging from 27.8-55.11µM, and in four HGSOC patient-derived organoids ranged from 14.52-42.27µM. Interestingly, COV362 cells that have a BRCA1 mutation and HRD, displayed the highest IC50 to efavirenz in both 2D and 3D models. The percentage of cells in sub-G1 and G1 phase increased after 35µM and 45µM doses of efavirenz, indicating an increase in stalling in G1. Conclusions and Implications: Efavirenz may be a viable therapeutic option for HGSOC independent of HRD

Historically in a pandemic the focus has been upon identifying agents that would eliminate the invading species with as little damage as possible to the host. Recently discussion has moved, particularly with COVID-19, from antiviral therapy to delineating the treatment of the host from treatment. With the latter, the approach brings together three concepts; treating the host, the damage response framework and therapeutic repurposing. The integration of these three areas play heavily to the traditional strength of pharmaceuticals in providing a period of stabilization prior to the introduction of subsequent interventions to permit time for the development of novel anti-viral drugs and vaccines . In integrating approaches to repurposing, host treatment and damage response we identified three key properties that a potentially effective repurposed drug must posses by way of a framework. There must be homology with the pathogenesis of the disease, ideally targeted to the conserved pathophysiological outcomes of the vial attack, have a defined locus within the spectrum from prevention to severe disease and finally draw upon the historical dose and safety experience of the repurposed drug. By way of illustration we have mapped therapeutic agents that impact upon the renin angiotensin system using this approach. Collectively this type of analysis reveals the importance of existing data (repurposed information and administrative observational data) and the details of the known pathophysiology of the viral attack are in approaches to treating the host; and with COVID-19 the significance of a pre-existing RAS-mediated inflammatory disposition.