From Discovery to Recovery
Ovarian Focus Group
The Ovarian Focus Group is comprised of oncologists, gynaecological oncology surgeons, pathologists, geneticists and laboratory-based scientists. Its role is to facilitate the transition of novel biomarkers or therapies from the laboratory into prospective clinical trials run in the Belfast Experimental Cancer Medical Centre (ECMC).
Chair: Professor Richard Kennedy
|Dr James Beirne||Professor Tim Harrison||Dr Eileen Parkes|
|Dr Niamh Buckley (O'Brien)||Dr Nuala McCabe||Dr John Price|
|Dr Elaine Craig||Professor Karen McCloskey||Professor Tracy Robson|
|Dr Sharon Eddie||Professor Glenn McCluggage||Dr Kienan Savage|
|Dr Aya El-Helali||Dr Sarah McKenna||Professor Manuel Salto-Tellez|
|Dr Fiona Furlong||Dr Joanne Millar||Dr Claire Thompson|
|Professor Paul Harkin||Professor Patrick Morrison||Ms Laura Webster|
|Dr Ian Harley||Dr Paul Mullan|
Areas of Research Focus
Dr James Beirne and Dr Paul Mullan have focused on the discovery of blood biomarkers of HGSC, as this is an area of significant need.
Gene expression and DNA Methylation (DNAme) array profiling of formalin fixed paraffin embedded (FFPE) matched tissue samples from 6 cases of HGSC has been performed. Given the current consensus that the cell of origin of HGSC is actually the fallopian tubes, the tissues collected were: normal fallopian tube epithelium (FT), normal ovarian surface epithelium (OSE), serous tubal intraepithelial carcinoma (STIC), primary HGSC and omental metastases (OMT). RqPCR validation of target genes was initially performed including 14 novel secreted protein targets. Eight targets were selected to be taken forward into an ELISA-based screening experiment. Eight ELISAs were performed on a small cohort of serum samples from “normal” patients versus “HGSC” patients. They identified two targets that appear to be statistically significantly better than CA125 (routine NHS diagnostics) at discriminating “HGSC” from “Normal”.
Together with Almac Discovery, Professor Tracy Robson led the development of therapeutic peptide derivatives based on FKBPL’s active anti-angiogenic domain. ALM201, a ‘first-in-class’ FKBPL-based anti-angiogenic therapeutic peptide entered phase I/II cancer clinical trials in ovarian cancer in July 2015 (EudraCT number: 2014-001175-31) at centres in Belfast, Manchester and Newcastle; early indications in a handful of patients demonstrate that the drug has no dose-limiting toxicity, with some patients showing signs of stable disease.
Professor Richard Kennedy’s group have identified and validated a biomarker for activation of the MEKK pathway in ovarian cancer and have shown that this is an important determinant of primary and acquired resistance to carboplatin-based agents. This group has also characterised a novel immune response to abnormal DNA in ovarian cancer that upregulates expression of PD-L1 and may be a determinant of response to immune-checkpointing targeted therapies.
Professor Glenn McCluggage has been part of the last 2 WHO groups formulating the classification of Tumours of the Female Genital Tract. He has recently been involved in a group which has proposed criteria for assessment of primary site in extrauterine high grade serous carcinoma (papers in press in Gynecologic Oncology and International Journal of Gynecological Pathology).
Dr Fiona Furlong’s research focuses on the role of microRNA mediated mechanisms of chemoresistance in high grade serous ovarian cancer in which she has demonstrated that overexpression of the miR-433 microRNA mediates increase resistance to both paclitaxel and carboplatin in epithelial ovarian cancer cells. This work has led to the analysis of miR-433 and the miR-433 gene targets as biomarkers of chemoresistance in which she has screened ~500 tumour samples. She has also demonstrated that miR-433 is a critical regulator of the cell cycle in which it may have important tumour suppressor functions.
Dr Kienan Savage’s group has identified mutations in RNA splicing factors as potential biomarkers of risk for ovarian cancer. He is now collaborating with the Department of Genetics to validate these in families with familial ovarian cancer not due to BRCA1/2 mutations.
Dr Niamh Buckley and Dr Sharon Eddie have been working towards developing a number of different in vivo models of ovarian cancer. First they have used a modified cre/lox approach to developing a GEMM model. They can virally deliver cre recombinbase to the tissue of origin of interest into an in vivo model with floxed ovarian cancer specific genes (eg BRCA1). The advantage of this strategy over conventional promoter driven cre is that often it is very difficult to identify a tissue specific promoter that does not lead to “leaky” expression of cre and therefore gene knockout in other tissues. Furthermore, as lentivirus has a high packaging capacity, polycistronic vectors can be used to allow simultaneous overexpression or knockdown of additional genes. This can also be utilised to allow bioimaging though co-expression of luciferase or GFP. This group have spent considerable time obtaining both Home Office and Health and Safety approval. As this is now in place, pilot studies will be starting to establish latency periods etc.
In addition, they are obtaining a conventional cre/lox model whereby BRCA1 knockdown is under the control of Pax8 through our focus group collaborator, Professor Ronny Drapkin. This will provide an established model while the other viral driven model is being developed. A second approach is to use a murine derived fallopian tube cell line obtained through a focus group collaborator, Dr Joanne Burdette. These cells can be syngeneically allografted into immune competent host allowing us to study tumour/host interactions which is not possible using human derived xenograft models. The group are also currently developing a number of isogenic lines from these cells with modulation of key ovarian cancer genes and plan to utilise these in vivo.