Identification of biomarkers of drug response in soft tissue uterine sarcoma
Dr Ailith Ewing, Prof V Brunton, Prof C Gourley, Dr P Roxburgh
About the Project
Leiomyosarcoma is an aggressive malignancy with limited treatment options and no biomarkers of treatment response.1 However, poly-ADP ribose polymersase (PARP) inhibitors have shown promise in a subset of patients. Homologous recombination deficiency (HRD) is predictive of response to PARP inhibitors and genomic studies describe high frequencies of a HRD signature in leiomyosarcoma. This is due to the inability of HR deficient cells to effectively repair DNA damage induced by PARP inhibitors. PARP inhibitors have revolutionised clinical outcomes in tumour types such as high grade serous ovarian cancer (HGSOC), where around half of patients have an identifiable defect in the HR pathway, such as BRCA1/2 mutations. Structural variants are underappreciated genomic events that may amplify, delete or rearrange regions, with significant variability in size and complexity. We characterised BRCA1/2 structural variants using whole genome sequencing (WGS) in a large HGSOC patient cohort. We demonstrated that large deletions spanning BRCA1/2 contributed to HRD, independently of BRCA1/2 mutations. On analysis of the Pancancer Analysis of Whole Genome (PCAWG) dataset, we identified a high frequency of BRCA2 structural variants in leiomyosarcoma.2 Literature also suggests these structural variants may affect other DNA damage repair genes in leiomyosarcoma.
Despite supportive genomic, pre-clinical and clinical data, the exact biomarkers of HRD and PARP inhibitor sensitivity in leiomyosarcoma are unknown. The purpose of this research is to perform comprehensive genomic characterisation to match in vitro drug sensitivity data of DNA damage repair agents in a panel of primary patient-derived models of uterine leiomyosarcoma. This aims to identify genomic biomarkers of sensitivity to PARP inhibitors (which show promise in a subset of patients with leiomyosarcoma), and to identify other DNA damage repair agents of interest, alongside associated biomarkers of response. Genomic characterisation of uterine leiomyosarcoma will be split into the following aims:
- Analysis of WGS of patient samples, via Genomics England (access approved), PCAWG and other publicly available datasets to identify biomarkers of genome-wide predictors of HRD in leiomyosarcoma.
- Compare biomarkers of response between responders and non-responders from a PARP inhibitor clinical trial in leiomyosarcoma using matched transcriptomic and genomic sequencing data (whole exome) from highly valuable trial samples.
- Define genomic alterations in DNA damage repair pathways in patient derived xenograft (PDX) models of leiomyosarcoma using matched whole genome sequencing and RNAseq, and relate to in vitro drug sensitivity data of DNA damage repair agents from the same models.
Risks and mitigation: All sequencing data for Aims 1/2 are available either publicly or via collaborators. Generation of WGS from existing PDX models used for Aim 3 is the subject of a grant submitted to Sarcoma UK (PI: Brunton, response due March 2023). If this application is unsuccessful, Aim 3 will use matched whole exome sequencing and RNAseq from PDX models of uterine leiomyosarcoma publicly available via the NCI Patient-Derived Models Repository. Although not WGS these data will allow us to investigate copy number alterations at DNA damage repair genes as biomarkers for mutational predictors of HRD, discovered in Aim 1 and validated in Aim 2.
Up to 4 studentships are available to start in September 2023 for outstanding applicants with a stipend of £21,000 p/a. These 4 STUDENTSHIPS are funded by the CRUK Scotland Centre, a joint initiative between Edinburgh and Glasgow. Successful students for Edinburgh lead projects will be registered for their degree in Edinburgh and will undertake their project in Edinburgh.
Candidates should hold at least an upper second-class degree in a relevant subject and comply with University of Edinburgh English language requirements.
For further information on how to apply, please visit: https://www.ed.ac.uk/cancer-centre/graduate-research-and-training/cancer-research-uk-phd-programme