Prof Clare Scott AM, Lab Head | WEHI Researcher Profile

Q: Tailoring new treatments to DNA repair defects in aggressive ovarian cancer

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.

Q: Understanding protective features of individuals who respond exceptionally well to a broad range of rare cancer types or who develop multiple types of 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.

Q: In-depth multi-omic (single cell and spatial transcriptomics, and proteomics) analysis of the most aggressive gynaecological cancer, ovarian carcinosarcoma

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.

Q: Analysis of patient samples from the EPOCH trial: Eribulin plus pembrolizumab in ovarian and uterine carcinosarcoma

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.

Q: Using novel preclinical models to prioritise the most effective targeted therapy combinations for high-grade serous endometrial cancer (HGSEC) clinical trials

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.

Q: Identifying new treatments for DNA repair proficient high-grade serous ovarian cancer (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.

Q: Exploiting ferroptosis to augment current and potential new treatments for uterine leiomyosarcoma

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.

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About

I am a clinician scientist, leading the Ovarian and Rare Gynaecological Cancers laboratory at WEHI and working as a medical oncologist at the Peter MacCallum Cancer Centre, Royal Women’s and Royal Melbourne Hospitals.

My clinical expertise is in gynaecological cancers and coordinating care for patients with rare cancers. I have 25 years’ experience in clinical cancer genetics, working in Familial Cancer Clinics.

My laboratory focuses on making pre-clinical models in which to study drug resistance in rare gynaecological cancers. I set up the national WEHI Stafford Fox Rare Cancer Program in order to facilitate the study of many rare cancer types which are poorly researched. I set up the Australian Rare Cancer Portal so that expert rare cancer care and research could be streamlined for individuals, no matter where they live.

I believe that involving the community in research enhances the purpose of our research and magnifies the benefits of what we do.

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Selected publications from Prof Clare Scott AM

Nesic K, Krais JJ, Wang Y, Vandenberg CJ, Patel P, Cai KQ, Kwan T, Lieschke E, Ho G-Y, Barker HE, Bedo J, Casadei S, Farrell A, Radke M, Shield-Artin K, Penington JS, Geissler F, Kyran E, Betsch R, Xu L, Zhang F, Dobrovic A, Olesen I, Kristeleit R, Oza A, McNeish I, Ratnayake G, Traficante N, DeFazio A, Bowtell DDL, Harding TC, Lin K, Swisher EM, Kondrashova O, Scott CL, Johnson N, Wakefield MJ. BRCA1 secondary splice-site mutations drive exon-skipping and PARP inhibitor resistance. Molecular Cancer. 2024;23(1):10.1186/s12943-024-02048-1

Xu H, Gitto SB, Ho G-Y, Medvedev S, Shield-Artin K, Kim H, Beard S, Kinose Y, Wang X, Barker HE, Ratnayake G, Hwang W-T, Study AOC, Hansen RJ, Strouse B, Milutinovic S, Hassig C, Wakefield MJ, Vandenberg CJ, Scott CL, Simpkins F. CHK1 inhibitor SRA737 is active in PARP inhibitor resistant and CCNE1 amplified ovarian cancer. iScience. 2024;27(7):10.1016/j.isci.2024.109978

Smith RA, Slocombe J, Cockwill J, Minas K, Kiossoglou G, Gray K, Lawrence W, Iddles M, Scott C, O’Reilly LA. Patient and public involvement in preclinical and medical research: Evaluation of an established programme in a Discovery‐Based Medical Research Institute. Health Expectations. 2024;27(1):10.1111/hex.13968

Geissler F, Nesic K, Kondrashova O, Dobrovic A, Swisher EM, Scott CL, J Wakefield M. The role of aberrant DNA methylation in cancer initiation and clinical impacts. Therapeutic Advances in Medical Oncology. 2024;16:10.1177/17588359231220511

Abdelmogod A, Papadopoulos L, Riordan S, Wong M, Weltman M, Lim R, McEvoy C, Fellowes A, Fox S, Bedő J, Penington J, Pham K, Hofmann O, Vissers JHA, Grimmond S, Ratnayake G, Christie M, Mitchell C, Murray WK, McClymont K, Luk P, Papenfuss AT, Kee D, Scott CL, Goldstein D, Barker HE. A Matched Molecular and Clinical Analysis of the Epithelioid Haemangioendothelioma Cohort in the Stafford Fox Rare Cancer Program and Contextual Literature Review. Cancers. 2023;15(17):10.3390/cancers15174378

Marks ZRC, Campbell NK, Mangan NE, Vandenberg CJ, Gearing LJ, Matthews AY, Gould JA, Tate MD, Wray-McCann G, Ying L, Rosli S, Brockwell N, Parker BS, Lim SS, Bilandzic M, Christie EL, Stephens AN, de Geus E, Wakefield MJ, Ho G-Y, McNally O, McNeish IA, Bowtell DDL, de Weerd NA, Scott CL, Bourke NM, Hertzog PJ. Interferon-ε is a tumour suppressor and restricts ovarian cancer. Nature. 2023;620(7976):10.1038/s41586-023-06421-w

Nesic K, Krais JJ, Vandenberg CJ, Wang Y, Patel P, Cai KQ, Kwan T, Lieschke E, Ho G-Y, Barker HE, Bedo J, Casadei S, Farrell A, Radke M, Shield-Artin K, Penington JS, Geissler F, Kyran E, Zhang F, Dobrovic A, Olesen I, Kristeleit R, Oza A, Ratnayake G, Traficante N, Study AOC, DeFazio A, Bowtell DDL, Harding TC, Lin K, Swisher EM, Kondrashova O, Scott CL, Johnson N, Wakefield MJ. BRCA1 secondary splice-site mutations drive exon-skipping and PARP inhibitor resistance. 2023;4(03-29):10.1101/2023.03.20.23287465

Vandenberg CJ, Rybinski K, Nesic K, Lim R, Neagle C, Ho G-Y, Ratnayake G, Papenfuss AT, Furuuchi K, Barker HE, Scott CL. Preclinical testing of farletuzumab ecteribulin (FZEC [MORAb-202]) and MORAb-109, folate receptor α and mesothelin targeting antibody-drug conjugates (ADCs), in rare gynecologic cancers.Journal of Clinical Oncology. 2023;41(16_suppl):10.1200/jco.2023.41.16_suppl.e17634

Sjoquist KM, Dobrovic A, Robledo K, Baron-Hay SE, Ananda S, McCarthy NJ, Goh JC, Murray N, Steer CB, Yip S, Mileshkin LR, Kondrashova O, Fink JL, Chang G, Bailey L, Lee Y, Zebic DS, Vandenberg CJ, Scott CL, Waring PM. Olaparib in HR-deficient (HRD), metastatic triple-negative breast cancer (TNBC) and relapsed ovarian cancer (ROC) without germline mutations in BRCA1 or BRCA2: Phase 2 EMBRACE trial.Journal of Clinical Oncology. 2023;41(16_suppl):10.1200/jco.2023.41.16_suppl.e15079

Dall G, Vandenberg CJ, Nesic K, Ratnayake G, Zhu W, Vissers JHA, Bedő J, Penington J, Wakefield MJ, Kee D, Carmagnac A, Lim R, Shield-Artin K, Milesi B, Lobley A, Kyran EL, O’Grady E, Tram J, Zhou W, Nugawela D, Stewart KP, Caldwell R, Papadopoulos L, Ng AP, Dobrovic A, Fox SB, McNally O, Power JD, Meniawy T, Tan TH, Collins IM, Klein O, Barnett S, Olesen I, Hamilton A, Hofmann O, Grimmond S, Papenfuss AT, Scott CL, Barker HE. Targeting homologous recombination deficiency in uterine leiomyosarcoma. Journal of Experimental & Clinical Cancer Research. 2023;42(1):10.1186/s13046-023-02687-0

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Lab research projects

Tailoring new treatments to DNA repair defects in aggressive ovarian cancer

Understanding protective features of individuals who respond exceptionally well to a broad range of rare cancer types or who develop multiple types of cancers.

In-depth multi-omic (single cell and spatial transcriptomics, and proteomics) analysis of the most aggressive gynaecological cancer, ovarian carcinosarcoma

Analysis of patient samples from the EPOCH trial: Eribulin plus pembrolizumab in ovarian and uterine carcinosarcoma

Using novel preclinical models to prioritise the most effective targeted therapy combinations for high-grade serous endometrial cancer (HGSEC) clinical trials

Identifying new treatments for DNA repair proficient high-grade serous ovarian cancer (HGSOC)

Exploiting ferroptosis to augment current and potential new treatments for uterine leiomyosarcoma

Student research projects

Studying tumour evolution and immune cell composition in uterine leiomyosarcoma to define novel effective combinations of targeted therapies

PhD

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Identifying effective combination therapies including HER2-targeting agents for the treatment of aggressive endometrial cancers

Honours

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Studying tumour evolution and immune cell composition in uterine leiomyosarcoma to define novel effective combinations of targeted therapies

PhD

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Identifying effective combination therapies including HER2-targeting agents for the treatment of aggressive endometrial cancers

Honours

More information

View all student research projects

Prof Clare Scott AM

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