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Dr
Rebecca Fitzgerald
Hutchison-MRC Research Centre
Cambridge
Rebecca Fitzgerald studied Medicine at Cambridge University and
gained her MD in 1997 following a period of research at Stanford
University, California, with Professor George Triadafilopoulos. Her
postdoctoral training took place at the Department of Adult and
Paediatric Gastroenterology, St Barts and The Royal London School of
Medicine and Dentistry with Professor Michael Farthing funded by an
MRC Clinician Scientist award. She is now an MRC Programme Leader at
the Cancer Cell Unit, Hutchison-MRC Research Centre, Cambridge and
Honorary Consultant in Gastroenterology and General Medicine,
Addenbrooke’s Hospital Cambridge.
Cancers of the oesophagus including those at the junction with the
stomach (gastro-oesophageal junction) have a very poor prognosis
because they tend to come to medical attention at an advanced stage.
However, many of these cancers have a precursor, or pre-invasive,
lesion and hence survival from these cancers could be dramatically
improved if we could intervene early. The oesophagus provides an
ideal opportunity to study the factors important in the natural
history of cancer from the eearliest stages. Firstly, the oesophagus
can be assessed easily using a fibreoptic instrument called an
endoscope. Secondly, there is a well defined
metaplasia-dysplasia-adenocarcinoma sequence in which the squamous
epithelium of the distal oesophagus is replaced by a columnar-lined
oesophagus called Barrett’s oesophagus in people who have reflux of
gastric and duodenal contents.
The
specific issues being addressed by Rebecca’s research programme are:
1) Can we identify high-risk groups for the development of Barrett’s
oesophagus and oesophageal adenocarcinoma? 2) Can we understand the
molecular pathogenesis of oesophageal carcinogenesis, using a
combination of in vitro cell biological assays and genomics, and
apply this understanding to clinical practice?
To
address the first question we are assessing molecular changes at the
level of the tissue. In order for molecular biomarkers to be applied
clinically for population screening and surveillance the search for
biomarkers needs to be combined with development of a robust,
cost-effective assay. In a pilot-study we have demonstrated the
feasibility of a non-endoscopic sampling method of the oesophagus,
using a capsule sponge device. We are now evaluating the role of
this method for screening within primary care (Barrett’s Esophagus
Screening Trial, BEST). This trial of 500 individuals with heartburn
symptoms explores the issues around recruitment, acceptability,
economics and sensitivity and specificity of the test as a prelude
for a larger trial. In parallel, we are evaluating biomarkers that
predict prognosis for patients with Barrett’s oesophagus and
associated adenocarcinoma.
For
the second aim we are utilising human model culture systems (ex vivo
and in vitro) that we developed previously, to evaluate the cell of
origin of Barrett’s oesophagus and the cell signalling pathways
involved. Our previous work has suggested that the cell
microenvironment may be an important determinant of cell phenotype.
Most of this work has focussed on the luminal factors (acid, bile)
and more recently we have demonstrated the luminal nitric oxide can
induce DNA damage. We are now evaluating the role of the stroma
which in combination with the lumen may be an important determinant
of cell fate and malignant potential. This will pave the way for
studies to examine whether cancer progression can be altered by
manipulation of these microenvironments.
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