Dr. Sharon O'Toole

Summary

Ovarian cancer is one of the most common cancers affecting women and is often detected in the advanced stage of the disease, resulting in a high mortality rate. This is because the symptoms of ovarian cancer are not recognised immediately, the molecular pathobiology of ovarian disease is poorly understood 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. Understanding the biological mechanisms underlying recurrence of ovarian cancer and addressing chemoresistance is of the utmost importance for improving treatment and outcome of the disease. Recurrence represents the "true killer" among ovarian cancer patients and identification of novel molecular markers present in recurrent tumours is urgently required. Using cDNA microarrays, we will carry out gene expression profiling between primary and recurrent ovarian cancers from different patients with the same histology and from the same patients with different histology aiming to identify potential biomarkers of recurrence. Using TaqMan PCR techniques, selected targets will be further validated to correlate with microarray results. Signatures from both cohorts will be also validated against an independent set of serous papillary ovarian adenocarcinomas, the most common histological subtype. Using real-time RT-PCR, we will also examine the patterns of dysregulation of miRNAs in recurrent ovarian cancer and we will elucidate potential mechanisms responsible for this dysregulation. We will observe for any possible intersections between our transcriptomic and miRNA targets. We will also investigate the in vitro effects of selected targets in platinum sensitive and resistant cell lines.

Funding Agency

Royal City of Dublin Hospital Trust Fund

Project Type

Basic Science

Summary

We have established an international trans-institutional multidisciplinary consortium [DISCOVARY] to address the problem of ovarian cancer. Our current work is focussed on identifying transcriptome, proteome and regulatory signatures which characterise early (Stage I), advanced (Stage III-IV), recurrent, chemoresistant and chemosensitive ovarian cancer and which can be used in a clinical setting to improve the diagnosis, treatment and management of this disease In addition, we believe that hypoxia plays a central role in the emergence of the chemoresistant phenotype in ovarian cancer patients. As part of our translational discovery pipeline, we have established the following specific objectives for this study: A. Extension and maintenance of a human ovarian tissue and serum bioresource network in Ireland, with the establishment of international collaborative link B. Generation of a novel human ovarian library proteome resource [OVA-1] C. Construction of a serum antibody profile in ovarian cancer D. Validation of a proteome map of borderline and early [stage I] ovarian cancer E. Construction of a transcriptome and miRNA translational control map of early, recurrent, non-recurrent and chemo-resistant ovarian cancer F. Formulation of diagnostic, prognostic and therapeutic validation pipelines G. Patient specific lab-on-a-chip devices to be used in therapeutic monitoring, bio-discovery and novel chemotherapeutic drug discovery H. Uncoupling hypoxia and chemoresistance in ovarian cancer I. Understanding blood-borne mechanisms involved in growth and spread of ovarian cancer J. Understanding cancer stem cells in ovarian cancer 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.

Funding Agency

Emer Casey Foundation

Summary

Co-investigator

Funding Agency

EU Commission

Programme

5th Framework

Summary

Funding Agency

Bristol-Myers Squibb/Enterprise Ireland