Ovarian cancer accounts for 4,200 annual deaths in the UK. Edinburgh and Glasgow have led recent landmark international clinical trials in low grade serous and clear cell ovarian cancers well as a study defining the molecular landscape of endometrioid ovarian cancer. They have also worked together in major genomic research in high grade serous ovarian cancer (HGSOC) to unravel mechanisms of PARP inhibitor resistance and sensitivity. We wish to leverage the pre-clinical modelling and genomics strengths across the two sites to identify new therapies in low grade serous ovarian cancer (LGSOC) and to refine the molecular classification and phenotypic correlates of HGSOC.

Identification of novel therapies for LGSOC (leads Gourley, Herrington, Coffelt, Sansom)

Unlike the commonest form of ovarian cancer (HGSOC), LGSOC affects younger women, is generally chemoresistant and has few effective standard of care treatment options. Our activity in this under-researched disease is nationally unique and internationally leading.

Although activation of the MAP kinase pathway underlies around 50% of LGSOC, the biology driving the remainder is unclear. Using translational research samples from the GOG281/LOGS study of MEK inhibitor trametinib (the first positive randomized trial in LGSOC), we will further characterize the LGSOC molecular landscape (exome sequencing of archival specimens and whole genome sequencing of fresh samples) and seek markers of MEK inhibitor sensitivity and resistance. Longitudinal development of resistance on therapy will also be interrogated using sequential ctDNA samples from the GOG281/LOGS study.

The Gourley Lab are currently conducting an in vitro high throughput drug screen to identify agents with anti-LGSOC activity (£190k, Target Ovarian Cancer) as single agents and in combination with trametinib (given the new standard of care established by the GOG281/LOGS study). After identification, the most active combinations will be evaluated in the Ptenfl/fl, KrasG12D murine model of LGSOC.  Using this immunocompetent mouse model will allow study of efficacy of the combinations and modulation of MAPK and relevant combination partner pathways between and within the tumour and the TME. The Centre has particular expertise in MAPK combinations in other key tumour themes (Sansom). 

Refine the molecular classification of HGSOC and establish the phenotypic correlates (leads Ewing, Semple, Glasspool, Carragher)

Although a greater understanding of some HGSOC molecular subgroups (BRCA1/2 mutant or homologous recombination deficient) has led to effective therapeutic strategies based on PARP inhibition, the role of other key molecular defects (e.g. CCNE1 amplification, RB1 loss, NF1 loss, PTEN loss) in harder to treat (homologous recombination proficient) HGSOC has not been adequately explored. The majority of these molecular defects arise as a result of structural variation, so large whole genome sequencing (WGS) datasets are required to investigate the phenotypic consequences of these defects, with the aim of subsequently informing novel targeting strategies. Leveraging WGS and RNAseq data from a cohort of 115 Scottish HGSOC patients (£1M CSO/AstraZeneca funding, see below) and accessing in silico cohorts, we now have a fully annotated 324 patient dataset. Through collaboration with the bioinformatics group at the MRC Human Genetics Unit (Semple, Ewing) we will interrogate this for the above molecular aberrations as well as gene fusion events, more complex structural variation such as chromothripsis, extrachromosomal DNA and mitochondrial DNA mutations. Centre funding will establish organoids to allow exploration of the phenotypic consequences of the key aberrations and will facilitate the identification of therapeutic vulnerabilities within these molecular subgroups (Carragher).

Identify strategies to abrogate PARP inhibitor (PARPi) resistance in HGSOC (leads Roxburgh, Zanivan, Bailey)

Unquestionably, PARP inhibitor therapy has resulted in a step-change in outcome for HGSOC patients with a realistic possibility of long-term disease-free survival for some patients. However, the majority of patients still progress. Whilst a number of PARPi resistance mechanisms have been identified in vitro the only mechanisms convincingly demonstrated to occur in patients are secondary mutations in BRCA1, BRCA2, RAD51C and RAD51D and loss of methylation of BRCA1 and RAD51C. In order to coordinate strategies to abrogate PARPi resistance it is imperative to understand the relative frequency of the various events driving resistance in patients. To uncover this, the Glasgow-Edinburgh-led PAIRS study (Wellbeing for Women/Artios Pharma, £1M) is being initiated. This will generate paired cancer material from 200 patients before and after the development of PARPi resistance. While genomic analysis is already funded, proteomic analysis will utilize the proteomic and informatics capabilities at the Centre (Zanivan, Bailey). In addition, the information derived from PAIRS will be applied to organoid models developed through the Centre (including some from PAIRS cohort A and cohort B patients) in order to explore further strategies of PARPi resistance abrogation.