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

Aim This Phase I open label study examined pharmacokinetics, safety, and tolerability of escalating doses of a combination cannabinoid medication (1:1 ratio THC:CBD) in patients with chronic non-cancer pain (CNCP) on high dose opioid analgesia. Methods Nine people with CNCP and oral morphine equivalent daily dose of ≥60mg were recruited. Blood concentrations of THC, 11-hydroxytetrahydrocannabinol (OH-THC), 11-nor-9-carboxy-tetrahydrocannabinol (COOH-THC) and CBD were assayed weekly. Concentrations were measured after a single dose of 2.5mg THC/2.5mg CBD up to 12.5mg THC/12.5mg CBD on Day 29. Follow-up was on Day 36 after 7 day washout. Secondary outcome data encompassed pain, mood, and sleep parameters. Results The parent THC, CBD, OH-THC, COOH-THC were detected at most time points. In general, the concentration of all analytes increased until 2 hours post-administration, decreasing to approximately pre-dose concentrations by 8 hrs. There was considerable inter- and intra-individual variability. The study medication was well tolerated. Eight participants reported at least one Adverse Event (AE), with a total of 62 AEs; most common were euphoric mood, headache, and agitation, none classified as severe. There was no significant change to pain severity self-ratings, nor use of pain medications. Improvements in pain interference scores, mood, and some sleep parameters were observed. Conclusion The THC:CBD formulation was tolerated well in a CNCP patient group. Between-participant variability supports personalized dosing and “start low-go slow” titration. Improvements in pain, mood, and sleep parameters suggest that on relatively low dosages clinical effects are apparent. To validate and quantify findings a comparison placebo group study is needed.