Ovarian & Rare Gynaecological Cancers Laboratory

Half of the aggressive ovarian cancer subtype, high-grade serous cancer (HGSC), have abnormalities in DNA repair and should be susceptible to new PARP inhibitor therapy, yet not all those respond.

By developing new models of studying human ovarian cancers in the laboratory (patient-derived xenografts, PDX, which have abnormal DNA repair), we are exploring which markers predict which ovarian cancers will respond best to these exciting new treatments and most importantly, how to prevent resistance to PARP inhibitors in some of these cancers.

Our starting point is to focus on different types of rare cancers and to look across many types of cancers, to see what is in common for individuals responding well to treatment or surviving better than would be expected.

We collaborate closely with Professor Tony Papenfuss and his team of bioinformaticians and with Professor Magdalena Plebanski, and her team at RMIT.

Ovarian carcinosarcoma (OCS) is a rare and aggressive type of ovarian cancer comprised of epithelial (carcinomatous) and mesenchymal (sarcomatous) components. It is believed that the sarcomatous component arises via a transdifferentiation of carcinomatous cells, in a process mediated by epithelial-to-mesenchymal transition (EMT). As the sarcomatous component drives the elevated chemoresistance observed with these tumours, uncovering how it forms is crucial to the development of effective targeted therapies. Therefore, single-cell RNA sequencing, spatial transcriptomics and proteomics analysis are being employed to elucidate the key genetic differences between the two components of OCS. By doing this, we hope to unravel what drives the sarcomatous transformation of carcinomatous cells, providing us with potential targets for treatment. We also hope to identify markers of partial EMT states which exhibit properties of both epithelial and mesenchymal cells, making them prime drivers of metastasis.

Ovarian carcinosarcoma (OCS) and uterine carcinosarcoma (UCS) are rare forms of gynaecological cancer associated with very poor prognoses. This is largely due to the lack targeted treatment options available for these tumour types, with most patients receiving cytoreductive surgery followed by platinum- and/or taxane-based chemotherapy with limited efficacy. The EPOCH clinical trial is attempting to evaluate the effectiveness of an eribulin and pembrolizumab combination treatment in relapsed OCS and UCS. Eribulin has previously been approved for use in metastatic breast cancer but also has been shown by our lab to modify the tumour microenvironment in OCS, as well as reverse EMT, a process believed to drive the formation of the most chemoresistant cells in these tumours. By combining this with pembrolizumab, a commonly used immunotherapy agent, we hope to improve prognoses for these tumours and identify potential biomarkers for treatment response.

High-grade serous ovarian cancer (HGSOC) with homologous recombination (HR) proficiency remains a major therapeutic challenge, as these tumours are less responsive to PARP inhibitors and standard chemotherapy. HR-proficient HGSOC represents up to 50% of HGSOC tumours. To address this major unmet clinical need, we leverage patient-derived samples, genomics, and preclinical models to identify novel drug vulnerabilities and mechanisms that can be exploited therapeutically. By integrating molecular profiling with functional assays and drug screens in cell lines, organoids and patient-derived xenograft mouse models, we aim to uncover precision medicine approaches that enhance treatment efficacy and improve patient outcomes. This research has critical clinical implications, offering new strategies for the treatment of HR-proficient HGSOC.

High-grade serous ovarian cancer (HGSOC) with homologous recombination (HR) proficiency remains a major therapeutic challenge, as these tumours are less responsive to PARP inhibitors and standard chemotherapy. HR-proficient HGSOC represents up to 50% of HGSOC tumours. To address this major unmet clinical need, we leverage patient-derived samples, genomics, and preclinical models to identify novel drug vulnerabilities and mechanisms that can be exploited therapeutically. By integrating molecular profiling with functional assays and drug screens in cell lines, organoids and patient-derived xenograft mouse models, we aim to uncover precision medicine approaches that enhance treatment efficacy and improve patient outcomes. This research has critical clinical implications, offering new strategies for the treatment of HR-proficient HGSOC.

Uterine leiomyosarcoma (uLMS) is a rare malignancy that is considered extremely aggressive and difficult to treat. Standard treatments involve surgery and chemotherapy but metastatic relapse is common and invariably fatal. Ferroptosis is distinct from more well-studied forms of cell death, such as apoptosis, necroptosis and autophagy. Ferroptosis is iron- and lipid-dependent and could potentially be harnessed to improve treatment responses in sarcoma. In this project, we will study gene expression at the single cell level, with spatial context, in a collection of uLMS samples collected from patients before, during and after therapy. We will focus on potential mechanisms of ferroptosis inhibition, which may have led to cancer therapy resistance. We will use our preclinical models of uLMS to test rational drug combinations involving ferroptosis inducers, to find better treatment options and support future clinical trial development.