Old and new pre-clinical tools to investigate mechanisms of drug resistance in ovarian and other rare gynaecological cancers

PROFESSOR CLARE SCOTT
Joint Division Head, Clinical Translation 
Walter and Eliza Hall Institute of Medical Research

Acquired resistance to the transformational therapy, PARP inhibitor (PARPi), in High Grade Serous Ovarian Carcinoma (HGSOC) commonly occurs via restored homologous recombination DNA repair due to secondary mutations in BRCA1/2 or loss of promoter methylation of BRCA1 or RAD51C. Overexpression of certain BRCA1 splice isoforms can also contribute to PARPi resistance in HGSOC. This includes the D11q isoform of BRCA1, where deleterious mutations in the 11q region of BRCA1 (exon 10) can be spliced out resulting in a truncated but partially functional BRCA1 protein. Pre-clinical models as well as clinical trial data addressing these forms of drug resistance will be presented.

Indeed, collectively, rare cancers (RC), such as subtypes of ovarian cancer, account for 22% of all cancer diagnoses and 30% of cancer deaths and are associated with poor outcomes and less evidence-based treatment. We designed the national WEHI-Stafford Fox Rare Cancer Program (SFRCP) to streamline RC research. We have instituted laboratory sample processing, including the generation of PBMCs, DNA, RNA, patient-derived xenografts (PDX) and PDX-derived organoids, associated with extensive NGS analysis, including by Whole Genome Sequencing (WGS) to underpin a range of rare gynaecological cancer projects to address these treatment disparities. We have performed WGS on 163 samples and will describe the implications of this sequencing, as well as presenting associated pre-clinical models of rare gynaecological cancers, including high grade serous endometrial cancer, uterine leiomyosarcoma, low grade serous ovarian cancer and vulval cancer.

Professor Clare Scott holds the Chair in Gynaecological Cancer at the University of Melbourne and is Joint Division Head of Clinical Translation and a Laboratory Head at the Walter and Eliza Hall Institute of Medical Research and Medical Oncologist at the Peter MacCallum Cancer Centre, Royal Women’s and Royal Melbourne Hospitals. She has 25 years’ experience in clinical cancer genetics, including working in Familial Cancer Clinics. Her clinical expertise is in gynaecological cancers and coordinating care for patients with rare cancers. Her laboratory focuses on drug resistance in ovarian cancer and other rare cancer types, generating patient-specific models to understand and avert resistance to targeted therapeutics. In particular, she has been a leader in developing PARP inhibitor therapy for ovarian cancer, which has resulted in unprecedented efficacy.

Professor Scott chairs the COSA Rare Cancer group and the Board of the International Rare Cancer Initiative (IRCI). She is also the Chair of the Australia and New Zealand Gynaecological Oncology Group (ANZGOG). Prof Scott has been awarded Clinical Fellowships from the Victorian Cancer Agency (2011, 2017), the Sir Edward Dunlop Cancer Research Fellowship from the Cancer Council Victoria (2012) and in 2018, the Jeannie Ferris Recognition Award in Gynaecological Cancer from Cancer Australia. In 2021, she was awarded the MOGA Novartis Oncology Cancer Achievement Award. She is a Fellow of the Australian Academy of Health and Medical Sciences. In 2022, Professor Scott was appointed a Member of the Order of Australia (AM) for significant service to gynaecological oncology.