Identification of biomarkers of drug response in soft tissue uterine sarcoma

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Leiomyosarcoma is an aggressive malignancy with limited treatment options.¹ However, poly-ADP ribose polymersase (PARP) inhibitors have shown promise in a subset of patients. Homologous recombination deficiency (HRD) is considered predictive of response to PARP inhibitors due to the inability of HR deficient cells to effectively repair DNA damage induced by PARP inhibitors, and genomic studies describe high frequencies of HRD in leiomyosarcoma. PARP inhibitors have revolutionised clinical outcomes in high grade serous ovarian cancer (HGSOC), where around half of patients have a 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 in a large HGSOC patient cohort and demonstrated that large deletions spanning BRCA1/2 contributed to HRD, independently of BRCA1/2 mutations. Analysis of the Pancancer Analysis of Whole Genome dataset 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.

This project aims to identify genomic biomarkers of sensitivity to PARP inhibitors, and to identify other DNA damage repair agents of interest, alongside associated biomarkers of response in leiomyosarcoma. Genomic characterisation of leiomyosarcoma will include analysis of whole genome sequencing of patient samples via publicly available datasets to identify biomarkers of genome-wide mutational predictors of HRD; comparison of  biomarkers of response between responders and non-responders from a PARP inhibitor clinical trial in leiomyosarcoma; definition of genomic alterations in DNA damage repair pathways in patient derived xenograft models of leiomyosarcoma, and their relation to in vitro drug sensitivity of DNA damage repair agents from the same models.

1. ¹George S, et al. J Clin Oncol (2018) 36(2):144-150.
2. ²Ewing A, et al. Clin Cancer Res (2021) 27(11):3201–3214.