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Ovarian Cancer

Ovarian Cancer

Ovarian cancer is the leading cause of death from gynaecological malignancy in the western world. About 200,000 cases of ovarian cancer occur worldwide each year with over 350 new cases in Ireland. The majority of ovarian cancer patients present in advanced stages (III or IV). This is because the symptoms of ovarian cancer are not recognised immediately and sensitive screening tests are not currently available. Treatment usually involves surgery followed by chemotherapy. While many women respond well initially, a worrying number of women will face a recurrence of disease, often with the tumour becoming less amenable to chemotherapy over time.

Emer Casey Foundation Logo

The DISCOVARY consortium was formed to specifically address issues in relation to ovarian and endometrial cancer diagnostics and prognostics and supports the development of translational research in Ireland. The consortium is built on ongoing collaborations between gynaecologists, oncologists, pathologists, scientists and bioinformaticians throughout Ireland, representing the following institutions, Obstetrics and Gynaecology, Histopathology, IMM, TCD; The Conway Institute, UCD; Biomedical Diagnostics Institute, DCU; Centre for Cancer Research and Cell Biology, Queens University Belfast and the following hospitals; St James’s, The Coombe Women and Infants University Hospital, The Mater, St Vincents University Hospital, Belfast City, University College Hospital Galway and University College Hospital, Cork. The consortium has the backing of ICORG and the Irish Cancer Society. The consortium has been fortunate to receive funding from the Emer Casey Foundation. Family and friends of Emer established the foundation following her untimely death from ovarian/uterine cancer in June 2006.

Various projects are being carried out under the umbrella of the DISCOVARY consortium and are detailed below.

Identification and validation of novel serum biomarkers for ovarian cancer (Emer Casey PhD Fellow Mairead Murphy)

This project involves screening bloods from ovarian cancer patients in an attempt to identify novel markers, which can be used to diagnose ovarian cancer at an early stage, to discriminate between malignant and benign disease and to diagnose recurrent disease.

Developing novel therapeutic approaches in chemoresistant ovarian cancer patients and investigation of the role of hypoxia in ovarian cancer chemoresistance using a novel lab-on-a-chip device (Emer Casey PhD Fellow Lynda McEvoy in collaboration with Biomedical Diagnostics Institute, Dublin City University)

chemoresistanceUnderstanding the biological mechanisms underlying chemoresistance and recurrence of ovarian cancer is an important goal. This will involve establishing the role of previously identified genes and miRNAs in the pathogenesis of ovarian cancer and recurrent ovarian cancer. A possible cause of chemoresistance is the microenvironment of the tumour, which is characterised by areas of poor oxygen supply known as hypoxia. The results of various experimental studies suggest that tumour hypoxia plays an important role in the development of typical features of malignancy such as invasiveness, metastatic potential, and resistance to treatment. An understanding of the key elements and control of the hypoxia pathway could reduce unnecessary chemotherapy treatment and toxicity, prolong survival and lead to more effective therapy for ovarian cancer. This project is also directed at employing a lab-on-a-chip device to test tumour cells for their response to chemotherapy prior to treatment. Our overall objective is to identify panels of markers that would define if an ovarian tumour will respond or be resistant to chemotherapy or if it will recur.

Hsa-miR-141 and hsa-miR-223 are central to Ovarian Serous Carcinoma Pathogenesis through Regulation of JAG1 and SMARCD1 proteins (Lisa Keogh)

The group has examined microRNA expression profiles with a view to distinguishing ovarian and primary peritoneal serous carcinoma histotypes. We are focussing our attention on specific gene regulators in this project. We believe they become over-expressed when the cancer genes are switched off. In this project we hope to conclusively prove this phenomenon using cells grown in culture. We will then test a large series of ovarian cancers to monitor levels of regulator molecules. To confirm our findings we will also examine a series of ovarian cancers for specific cancer promoting genes and their protein products.

miRNA Profiling in Ovarian Cancer Serum (Ream Langhe)

There is emerging research about the role of microRNAs in a variety of pathologic conditions; including both solid and hematologic malignancies. miRNA profiling has allowed the identification of signatures associated with diagnosis, prognosis and response to treatment of tumours. miRNAs have not been extensively studied in ovarian cancer and we propose to examine expression in serum of ovarian cancer patients. We intend to profile miRNAs in malignant, recurrent, borderline and benign disease and compare this to age matched controls. Functional studies will also be performed to establish how the miRNAs work

Cell cycle regulatory proteins and their potential role in early diagnosis, treatment and prognosis of borderline and invasive ovarian cancer (Alhadi Araibi)

Borderline tumours are a well delineated and clearly defined group of epithelial ovarian tumours. Their potential for progression is currently unknown. They can also recur early and in an aggressive manner. Tumorigenesis is a result of aberrant decisions in cell fate. Cells can improperly differentiate, resulting in tumour progression, or uncontrollably proliferate, resulting in tumour growth. MCMs, CDC6, CDt1, Geminin, P16 and NuF2 are some of the cell cycle regulatory proteins that have been extensively assessed and found to be differentially expressed in various tumours including breast, uterine cervix, colorectal and prostatic cancers. Their level of expression and significance in ovarian cancer remains to be elucidated in this project.

Pro-inflammatory pathways and differentiation in ovarian epithelial cancer – a model of cancer stem cells, hypoxia and chemoresistance (Charles d'Adhemar)

Toll-like-receptors (TLR’s) act as an immune pattern recognition system. Once stimulated they produce a pro-inflammatory response involving activation of MyD88 and NFkB molecules with the elaboration of cytokines, chemokines and growth factors. From a cancer cell perspective, such an environment forms an ideal paradigm for malignant progression. This project aims to investigate the significance of pro-inflammatory pathways in epithelial ovarian cancers to define whether manipulation of hypoxic and inflammatory conditions may result in a therapeutically relevant reduction of proliferation, as well as increased differentiation of ovarian malignancy towards less aggressive phenotypes.

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Last updated 21 September 2016 Paul Smyth (Email).