CRUK Scotland Centre – Developing patient-relevant models of poor prognosis high grade serous ovarian cancer (HGSOC)

Project description

There are 7500 new ovarian cancer cases in the UK per year making it the 6th most common cancer in females. Although ovarian cancer survival is improving, 5-year survival rates remain poor (42.6%). High-grade serous ovarian cancer (HGSOC) is the most common and lethal form of ovarian cancer. It is characterised by almost ubiquitous TP53 aberrations, cell-cycle defects, huge copy number change and genomic instability. We recently demonstrated two pathways to genomic diversity in HGSOC (1). One (approximately 50% of patients) is through homologous recombination deficiency (HRD); these tumours largely respond to platinum/PARP inhibitors. The other group of cancers is characterised by whole genome duplication (WGD) and is associated with chromothripsis, extrachromosomal DNA harbouring oncogenes, mitochondrial DNA mutations and CCNE1 amplification; these tumours are less likely to benefit from platinum/PARPi therapy and therefore understanding and developing effective therapies for this HGSOC sub-group is a major unmet need.

Genetically engineered mouse models of selected types of HGSOC have already been developed. To date they represent BRCA1/2 driven, HRD, HGSOC reasonably well however no model exists that recapitulates the structural genomic diversity seen in the poorest prognostic HGSOC sub-groups. In this project we therefore plan to develop novel, patient-relevant models of WGD HGSOC. Activation of mutational events seen in WGD HGSOC such as ecDNA-Myc, CCNE1 and mitochondrial mutations will be recapitulated in mouse models which will then be fully characterised to ensure that they are representative of the corresponding sub-type in humans, from a pathology, molecular and disease spectrum angle. Then after understanding the model and disease progression, we will use these realistic models to test rational treatments in an effort to identify new, more effective treatment strategies for this poor prognostic sub-group of patients.

The student will work in Professor Blyth’s group which is world leading in the development of mouse models of cancer and attached to the MRC National Mouse Genetics Network. The student will also be supported by Professor Semple from University of Edinburgh who is a bioinformation with expertise in structurally diverse cancers (mesothelioma and ovarian cancer) and Professor Patricia Roxburgh who has expertise in treatment of ovarian cancer and development of new cancer therapeutics, and who will ensure clinical relevance to the project.

The student will gain expertise in development and analysis of genetically engineered mouse models of cancer, translational preclinical models, immunohistochemistry, genomics and computational methods to interrogate biological data. They will also access the research training programme provided by the Universities of Glasgow and Edinburgh and actively participate in the ovarian theme of the CRUK Scotland Centre including attending regular joint Edinburgh-Glasgow meetings and presenting their findings internally and externally at conferences.

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Funding Notes

The CRUK Scotland Centre studentships are for 4 years and provide an annual tax-free stipend of £22,500 + 1.75% indexation in Year 2,3&4, university tuition fees and a consumables budget.