Novel therapeutic strategies to treat high-grade serous ovarian carcinoma by targeting modulators of PAR dynamics

Abstract

High-grade serous carcinoma (HGSC) is the commonest form of ovarian cancer, accounting for around 70% of all malignant ovarian tumours. Most cases of HGSC present with advanced disease, in which cure is unlikely. Standard treatment includes cytoreductive surgery plus platinum/taxane-based chemotherapy, with maintenance treatments used in certain subgroups. In particular, poly(ADP-ribose) polymerase-1/2 inhibitor (PARPi) therapy has demonstrated highly impressive improvements in survival outcomes, with the greatest benefits seen in patients diagnosed with a BRCA1/2 mutation. The success of PARPi treatments for HGSC exemplifies the therapeutic potential of targeting poly-ADP-ribosylation in this disease. Polymers of ADP-ribose are assembled by PARP-1/2 and subsequently degraded by the poly(ADP-ribose) glycohydrolase, PARG. In my thesis, I advance the use of PARPi and PARG inhibitors to treat HGSC. Firstly, I complete a single centre, phase II trial, investigating the use of multi-maintenance olaparib therapy in relapsed BRCA-mutant HGSC. Furthermore, I report the results from a biomarker study, built in to the trial, which aimed to optimise the use of olaparib through the detection of functional Homologous Recombination (HR) repair status, BRCA reversion mutations and somatic copy-number alteration (SCNA) in tumour and liquid biopsies. The results of this trial show that a second course of olaparib maintenance therapy is safe, but only modestly efficacious. Moreover, that neither functional HR status nor SCNA predicts response to platinum-olaparib therapy. Secondly, I use a ‘Living Biobank’ of patient-derived ex vivo ovarian cancer models (OCMs) to investigate in vitro sensitivity of the PARG inhibitor, PDD00017273 (PARGi). Here, I demonstrate that small molecule inhibition of PARG offers a potential therapeutic strategy for HGSC. To achieve this, I validate 24 OCMs as bona fide models of HGSC using clinically-defined diagnostic criteria. Next, using cell proliferation assays I demonstrate that approximately 20% of OCMs are sensitive to PARGi. Then, I show that through on-target activity, PARGi causes replication stress in sensitive OCMs, ultimately leading to replication catastrophe. Finally, I report that PARGi-sensitive OCMs can be used to generate patient-derived xenografts (PDXs) that possess the histological hallmarks of HGSC. Future research will be able to use these PDX models to investigate in vivo sensitivity of small molecule inhibitors of PARG. Taken together, these two projects advance the use of PARP-1/2 and PARG inhibitors to treat HGSC.

Date of Award	14 Dec 2021
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Caroline Springer (Co Supervisor), Gordon Jayson (Co Supervisor) & Stephen Taylor (Main Supervisor)