manchester cancer research centre · 2013-10-17 · aberrations in this communication process can...
TRANSCRIPT
Manchester Cancer Research Centre
Progress ReportNovember 2010
In this report wereview achievementsand progress over thepast year. Despite thecurrent challengingenvironment faced byus and many otherresearch institutions,we are continuing toexpand our researchactivities throughrecruitment ofpromising andexperienced staff,development of newareas of research andenhancement ofexisting facilities.
New recruits to the Manchester
Cancer Research Centre (MCRC)
will increase our capabilities in
tumour specific areas, such as
breast and lung cancer research
with a focus on the investigation
of signalling networks that play a
key role in the development and
progression of cancer. In addition,
our imaging research has been
strengthened, enhancing our
knowledge of and proficiency in
the use of this important
technology in planning and
delivering treatment and
monitoring patient response to
therapy.
We are also continuing to develop
new areas of research throughout
the MCRC partnership. In
particular, the new Drug Discovery
Centre is now well established and
has initiated novel and exciting
drug discovery programmes. The
expertise and advice the Centre
brings will be invaluable in
allowing us to assess the
therapeutic potential of our
research and in validating
prospective targets for therapeutic
intervention. The creation and
realisation of the Drug Discovery
Centre has generated and will
foster a drug-hunting culture
throughout the MCRC, ensuring
that our research has the end user,
the patient, at the core of its
strategy and promoting clinically
relevant basic and translational
research.
Building for the future remains a
key goal of the MCRC: these future
developments require major
capital investment in new
facilities. Both short and long
term projects are in progress
including the Patient Treatment
Centre, a £35 million facility built
by The Christie NHS Foundation
Trust, which is due to open ahead
of schedule before the end of the
year. This Centre incorporates a
dedicated early phase clinical trials
unit, which will be the largest such
facility in the world and will boost
our clinical research activities. In
the longer term, plans for a new
dedicated and forward-looking
research facility for the MCRC
partnership are well underway.
The past year has been both
productive and encouraging -
working together in a truly
collaborative manner has reaped
rewards for MCRC researchers,
which in the future will drive
tangible benefits for patients.
Professor Nic Jones
Director
Overcoming Challenges to DriveProgress
Ma
nch
est
er
Ca
nce
r R
ese
arc
h C
en
tre
Manchester Cancer Research Centre - Progress Report
New Group Leaders Recruited
3
Manchester Cancer Research Centre - Progress Report
Dr John Brognard, who was
previously based at the Salk Institute for
Biological Studies in San Diego, joined
the Paterson Institute for Cancer
Research as a Junior Group Leader in
August 2010.
His research focuses on new signalling pathways involved
in tumourigenesis, the process involved in the production
of new tumours. Dr Brognard’s future plans are aligned
with the signalling networks important in the initiation
and progression of lung cancers, which will complement
the Manchester Cancer Research Centre’s lung cancer
research initiative.
Dr Pengfei Paul Lu, from the
University of California San Francisco,
took up a position as Group Leader in
the Breakthrough Breast Cancer
Research Unit, which is part of The
University of Manchester’s School of
Cancer and Enabling Sciences.
He has a background in developmental biology and is
studying the function of potential tumour suppressor
genes in both the epithelium and stroma of the breast.
Cell-cell and cell-stroma communication and interaction
play an important role in normal tissue development and
aberrations in this communication process can lead to
the development of cancer. Dr Lu’s research focuses on
understanding the roles of the stromal
microenvironment in regulating adult stem cells, and on
the maintenance of epithelial polarity - a key feature of
organ integrity, the loss of which is often seen in breast
cancer. In addition, his research explores the role and
regulation of receptor tyrosine kinase (RTK) signalling in
mammary gland epithelium-stroma interactions, an
important signalling pathway that is often abnormally
regulated in many breast cancers. Dr Lu’s research will
augment breast cancer research ongoing within
Manchester.
Professor Michael Lisanti has been recruited
as Chair of Cancer Biology within the School of Cancer
and Enabling Sciences at The University of Manchester;
he will also be a member of the Breakthrough Breast
Cancer Research Unit.
Professor Lisanti is currently based at the Kimmel Cancer
Center in Philadelphia and will take up the position later
this year. He is a world expert in the identification and
characterisation of prognostic biomarkers in breast
cancer and his recruitment significantly strengthens
areas of breast cancer research and biomarker research,
both of which are high priorities for the MCRC.
Professor Mike White, founder of the Centre for
Cell Imaging in the School of Biological Sciences at
Liverpool University, has recently been recruited to the
Cellular Systems Division of the Faculty of Life Sciences at
The University of Manchester and awarded the Chair of
Systems Biology.
His research focuses on understanding the dynamics and
integration of cell signalling, transcription and cell fate in
mammalian cells with a particular emphasis on cell
division and apoptosis. Professor White will be
establishing a state-of-the-art Systems Imaging Centre
that will have cutting-edge technologies needed to push
the boundaries of live cell imaging. Research at the new
Centre will incorporate fast dynamics, which aims to
measure the structure and dynamics of molecules during
important biological processes, and will also incorporate
single cell approaches. It is anticipated that his research
team will be fully established in Manchester around
spring 2011 and will undertake studies that expand the
imaging research base within the MCRC, a technique that
plays an increasingly important role in planning and
guiding cancer treatment and monitoring patient
response to therapy.
Manchester Cancer Research Centre - Progress Report
In simple terms, small molecule drugdiscovery programmes seek outchemicals that have the potential tobecome clinically useful drugs byinteracting with, and altering theactivity of, a target in a beneficial,reproducible and safe way.
The challenge is identifying clinically relevant targets,
finding small molecules that interfere with the target’s
activity and then optimising them so that they can be used
in the treatment setting – a challenge being taken up by the
Drug Discovery Centre at the Paterson Institute for Cancer
Research.
With the aid of an £8 million 5-year funding programme
from Cancer Research UK (CR-UK), the newly established
Drug Discovery Centre can already list some notable
achievements. Under the leadership of Dr Donald Ogilvie,
the Centre has developed a clear strategy to deliver its long
term objectives. A crucial first step was to provide a state-
of-the-art facility able to meet existing and future needs,
and a new drug discovery laboratory has been built and
equipped on time and within budget, as Dr Ogilvie
explained: “At the start of this programme grant (April
2009), there were no suitable facilities for the Centre within
the Paterson Institute but a large vacant laboratory was
made available for refurbishment. Since provision of a
laboratory was an obvious rate-limiting step for
establishing the programme, we initiated the design phase
immediately,” he said.
A key feature of the laboratory design is co-localisation of
bioscience and chemistry activities within the same
laboratory to facilitate close communication between those
who design and synthesise, and those who test,
compounds. The use of expert consultancy design services
and the selection of equipment compatible with existing
facilities delivered both cost and time savings – a major
consideration in the current funding climate. The
laboratory was completed and handed over on schedule in
December 2009 and was equipped and ready for use in just
one month. Further cost savings were made through
supplier negotiation and where appropriate sourcing pre-
owned equipment, enabling the bioscience and chemistry
teams to be fully operational soon after handover of the
refurbished laboratory and only nine months after award of
the grant. Another achievement has been the timely
recruitment of a highly skilled core team enabling
laboratory work to begin in January 2010. After a
competitive and rigorous selection process, five
medicinal/synthetic chemists (led by Head of Chemistry, Dr
Allan Jordan) and four bioscientists have been appointed.
Importantly all the new recruits have industrial experience,
mainly in drug discovery, and the aim is to double team
numbers by April 2011 when additional funding is made
available.
As part of the strategy for drug discovery, key partners able
to deliver technology, materials and expertise, have been
identified. “Many of these interactions exploit the benefits
of our location in Manchester. We have particularly
benefited from the MCRC, which has opened many doors in
The University of Manchester – and our location in the
Paterson Institute adjacent to The Christie NHS Foundation
Trust with direct access to cutting edge basic science and
clinical expertise,” said Dr Ogilvie. A further benefit of the
location of the Centre has been in the selection of targets
for drug discovery projects. “Evaluating the clinical
relevance of targets is paramount and this is where our
close proximity to clinical expertise at The Christie has been
invaluable. We want to focus our efforts on discovering and
developing drugs that will fill an unmet medical need so the
clinical setting is the rational starting point,” explained Dr
Ogilvie. Drawing on the expertise within the MCRC, a
target selection strategy has been developed and presented
broadly across the MCRC leading to the identification of
specific targets and priority drug discovery projects that are
now underway.
Drug Discovery Centre – Where Small is Beautiful
4
Target selection is the first step in drug discovery. This is
followed by identification of chemical compounds (known
as hits) that interact with the target using techniques such
as high throughput screening where thousands of
compounds are screened simultaneously – the few hundred
that ‘hit’ the target are then potential leads. Another
method for generating hits is virtual screening based on the
structure of the target, running a database search to assess
which known chemicals might interact with the target.
Hits are confirmed by retesting and those that combine an
ability to interact with the target with the most attractive
properties, such as chemical stability, are chosen for lead
progression. The hits are further optimised, building a
chemical with improved potency, target specificity and
properties likely to make it pharmacologically active. These
optimised leads are then taken into preclinical and
ultimately clinical testing to assess their benefit.
The researchers are using high-throughput screening and
virtual screening and have now accessed capabilities in
both techniques. Given the large numbers of chemicals
screened and validated, drug discovery projects generate a
wealth of data making optimal information management a
priority. The Drug Discovery Centre has selected cutting
edge informatics company Dotmatics Limited to provide a
complete range of drug discovery informatics solutions,
including their newly released electronic laboratory
notebook system. This enables the capture, analysis and
interrogation of both the biological and chemical
information generated within the Centre. It also allows the
scientists to make informed decisions around the best
compounds to advance into further studies and ultimately
into the clinic. Implementation of the informatics
programme has been supported by the recruitment of a
highly experienced computational chemist.
“What we now have available (in Manchester, and within
the MCRC partnership) is the ability to identify specific
unmet needs or unanswered questions that present real-
life issues in the clinic. We can then undertake basic and
preclinical research to identify the molecular basis of these
issues and feed the molecular insight, in the form of targets,
into drug discovery projects to develop leads for preclinical
and then clinical testing in robust trials. With the on-site
expansion of early phase clinical trials and biomarker
capability, this is the ideal place to be driving successful
drug discovery programmes to completion,” said Dr Ogilvie.
Manchester Cancer Research Centre - Progress Report
5
The new £35 million Patient TreatmentCentre at The Christie NHS FoundationTrust, which is to open ahead ofschedule by Christmas this year, will behome to the largest early clinical trialsunit in the world and completes plansfor a three-fold expansion of facilities forearly phase clinical trials.
With the opening of these new facilities and planned future
growth in research staff, more patients will be able to have
early access to new therapies. Building work began on the
Patient Treatment Centre early in 2009 at The Christie’s main
site in Withington and the MCRC partners are eagerly
awaiting the formal opening.
As Professor Malcolm Ranson, Clinical Director of The
Christie’s Clinical Trials Unit explains: “Robust clinical trials
are essential in evaluating innovative treatment. The
remarkable progress made in basic cancer biology is
beginning to be translated into new therapies and we have
focussed on delivering true “bench to bedside” medicine.
The MCRC partners have been successful in building world-
class research teams alongside the necessary infrastructure
to bring this to fruition. With this expansion in our clinical
trials capacity we will be now be able to increase the number
and range of trials that we can offer patients”.
The Patient Treatment Centre, which attracted £4.2 million
funding from Cancer Research UK, also brings under one roof
early phase research and service chemotherapy making the
patient treatment pathway more convenient and efficient.
“We have tried to achieve both closer integration and a wider
understanding of the importance of clinical and translational
research. Having a facility designed from the outset to
facilitate this has been a major achievement,” added
Professor Ranson.
Manchester Cancer Research Centre - Progress Report
6
Patient Treatment Centre Triples Spacefor Early Clinical Trials
Manchester Cancer Research Centre - Progress Report
7
The inaugural MCRC Conference:Harnessing Apoptosis, which took placein January 2010, featured a plethora ofeminent international scientists whogave insight into the basic, translationaland clinical research ongoing tounderstand the mechanisms ofcontrolled cell death (apoptosis), whichis often aberrant in cancers.
Some 120 attendees gathered in Manchester for the
successful event and were treated to a wide range of talks
and facilitated discussions highlighting how new knowledge
in basic apoptotic mechanisms is transforming translational
studies and clinical trials in cancer. The meeting opened
with a plenary lecture by Doug Green, from St Jude Children’s
Research Hospital in Memphis, which focused on the
mitochondrial pathway of apoptosis, a major route for cell
death during development, homeostasis, and aging, and
upon physiological or pathological stress in vertebrates.
Following talks provided an overview and discussion of
proteins involved in apoptotic pathways such as Inhibitor of
APoptosis (IAP) proteins and BCL-2, highlighting that
understanding how cancer cells overcome apoptotic signals
is key to developing anticancer strategies based on
overcoming cancer cell insensitivity to apoptosis.
The conference also featured updates on the latest clinical
developments aimed at enhancing cancer cell apoptosis and
on biomarkers for early phase trials with apoptosis
endpoints. In addition, alternative cell death pathways were
reviewed, cell signalling pathways were evaluated and the
insights gained using cancer models were discussed. The
four-day conference concluded with a plenary lecture by
Karen Vousden, from the Beatson Institute for Cancer
Research in Glasgow, on the increasingly complex role of the
tumour suppressor p53 protein in the prevention of cancer
development. Harnessing Apoptosis was a great success; it
showcased the high quality cancer research in this area
whilst stimulating some very interesting discussion and
debate.
MCRC Conference: Harnessing Apoptosis
8
One year on and the MCRC ImagingGroup’s focus on multidisciplinary andclinically relevant research is payingdividends.
The Group has taken a three-pronged approach to their
research strategy with an emphasis on enhancing
biomarker studies, preclinical imaging and translational
imaging capability. Encouraging progress has already been
made across all three strategic goals.
A recurring theme within the Imaging Group is a new
approach to understanding cancer and identifying
appropriate targets for therapeutic intervention. “We are
looking at building a research strategy that has a rational
focus on the hallmarks that are characteristic across
tumour types. These include: proliferation, the cancer cell’s
ability to drive aberrant expansion; angiogenesis, the
process of new blood vessel development essential for
providing the nutrients that allow tumours to grow beyond
a critical size; and reduction in spontaneous apoptosis,
allowing the cancer to circumvent normal mechanisms of
programmed cell death,” explains Professor Alan Jackson,
from the University’s School of Cancer and Enabling
Sciences, who leads the Group.
This strategy means that research learnings will be
reproducible and relevant to a range of cancers, allowing
research insight to translate into novel approaches across
different tumour types. The Oglesby Charitable Trust, a
charity established in 1992 by Michael Oglesby, the Chair of
the MCRC’s Steering Board, recently funded a Clinical
Fellowship in Translational Oncology, which has been
Manchester Cancer Research Centre - Progress Report
MCRC Imaging Group: ResearchMotivated by Reality
Manchester Cancer Research Centre - Progress Report
9
awarded to Dr Ioannis Trigonis. Dr Trigonis is working on
developing methods to accurately measure tumour cell
proliferation rates in lung, breast and pancreatic cancer. He
aims to identify and validate biomarkers that can be used to
provide a baseline measure of tumour cell proliferation. The
research involves the use of Positron Emission Tomography
(PET) imaging, which provides a valuable three-dimensional
image of functional processes within the body, in
combination with the biologically active molecule
fluorothymidine (FLT) which is known to be an indicator of
proliferative activity. Tumours are heterogeneous so
different parts of the tumour exhibit different behaviours,
such as resistance to therapy due to lack of oxygen (tumour
hypoxia). Using FLT-PET will allow imaging of the tumour in
its entirety; visualisation of these different areas can be
combined with measurement of the proliferation rate of
specific areas. Another clinical project, led by Professor Karl
Herholz, aims to discover how inflammatory changes take
place in brain tumours using PK11195 PET, a PET technique
that has been applied in conditions such as stroke and
Alzheimer’s disease. This project is being carried out in
collaboration with The Walton Centre NHS Foundation Trust
in Liverpool, a specialist neuroscience centre.
“A major challenge in treating patients is understanding
and minimising therapeutic failure. Increasingly a key
clinical question is how does a tumour become resistant to
therapy and how we can identify and use biomarkers to
detect when resistance is likely, or when it occurs, so that
therapy can be rapidly changed before the patient
experiences relapse,” said Professor Jackson. Another
important aspect of optimising patient treatment and
outcome is monitoring response to therapy. The Imaging
Group aims to identify biomarkers that reflect changes in
the tumour in order to inform clinical decisions about the
success or progress of therapy, and to allow rational use of
treatments that are tailored to patient response. “The work
that Dr Trigonis is undertaking will provide valuable and
robust tools that can be validated and used across the
Imaging Group and across a range of tumours,” he added.
Preclinical imaging, led by Dr Kaye Williams from the
University’s School of Pharmacy, is focusing on
understanding metastatic behaviour and hypoxia – a
potent inducer of angiogenesis. The Group now have a
number of active PET imaging studies underway while
other joint projects have begun or are in the initiation
phase. These include the development of advanced
Magnetic Resonance Imaging (MRI) using cancer models,
one example being the recent successful implementation of
sodium imaging. Sodium imaging has a variety of medical
uses including non-invasive cartilage analysis to give an
indication of joint health, cellular viability in myocardial
ischemia (a lack of blood flow to the heart) and to track cell
death in cerebral infarction, a type of stroke. It has also been
used to differentiate tumours from surrounding tissue. One
project within the group aims to use advanced MRI to
develop and validate novel orthotopic models of brain
tumours, models that more realistically reflect the true
microenvironment that impacts tumour growth and
behaviour. To support these projects, the research teams
now have a new preclinical PET-CT scanner, a state-of-the-
art system that has now been installed and is fully
functional.
A translational imaging research group has been formed
providing a functional basis for clinical imaging research
and facilitating the translation of research findings to the
clinic. “The MCRC Imaging Group has a rational and
cohesive research strategy which is tightly aligned with
clinical need. We work to help understand the reasons for
and ways of overcoming clinical issues encountered in real
patients, such as resistance to therapy, by taking these
questions into the preclinical setting where we can
investigate their causes and identify potential solutions.
These solutions can then be tested in appropriate
preclinical models before entering early clinical trials and
finally, if found effective and safe, entering the clinic as a
new tool aimed at improving patient treatment and
outcomes,” concluded Professor Jackson. Manchester and
for cancer patients,” he said.
Highlights in Radiation-Related Research
Researchers involved in radiation-related research (RRR) within the MCRChave had a year of notable success andprogress and continue to deliver a co-ordinated and cohesive strategy.
The initiative launched last year by the UK’s National Cancer
Research Institute (NCRI) to develop and strengthen
translational RRR led to the establishment of a new Clinical
and Translational Radiotherapy Research Working Group
(CTRad), which aims to promote and support clinical trials
that have the potential to impact clinical practice. Professor
Tim Illidge, who leads RRR at the MCRC, will be taking on
the role of Chair of CTRad from October 2010, while Dr
Ranald Mackay, who leads North West Medical Physics at
The Christie NHS Foundation Trust, is co-chair of one of
CTRad’s four workstreams, focusing on new technology,
physics and quality assurance. Dr Mackay will be
overseeing the academic professional development of
physicists to optimally support improvements in RRR.
Professor Ian Stratford, who leads the Experimental
Oncology Group within the University’s School of Pharmacy,
with an emphasis on combining drugs and radiation, has
been appointed as national lead within the executive group
on radiation and drug combinations in cancer treatment.
Professor Stratford is leading the organisation of the 22nd
International LH Gray Conference ‘Realising the potential of
drug/radiation interactions’ in Manchester on 2-4 February
2011. “The choice of Manchester as hosts of this prestigious
international conference is a huge coup for the Manchester
RRR and NCRI CTRad groups. The programme features a
panel of international experts and will include sessions on
the biological aspects of radiotherapy targets and the
development of early phase trials with drug/radiation
combinations. In addition, participants will be able to
attend parallel workshops focusing on the optimisation of
trial design with radiotherapy and novel targeted agents,
and on the application of imaging in combined
drug/radiotherapy trials,” explained Professor Illidge.
The MCRC and AstraZeneca have worked together
productively through the MCRC/AZ alliance for several years
and the partnership has now led to the establishment of
two important RRR early phase clinical studies. The first of
these is the MEK/RT trial in patients with non-small cell
lung cancer (NSCLC), which has started patient recruitment.
Led by Dr Corinne Faivre-Finn at The Christie, the trial aims
to assess the efficacy and safety of the molecular targeted
MEK inhibitor (AZD6244) in combination with radiotherapy
in NSCLC patients with locally advanced or metastatic
disease as radiotherapy plays a major role in the treatment
of this patient subgroup. The second trial, the DREAM study
focuses on rectal cancer and is evaluating two drugs
developed by AstraZeneca with a novel study design; this
trial is being led by MCRC clinician Dr Mark Saunders, Chair
of the Gastrointestinal Tumour Study Group at The Christie.
“The DREAM study has a pioneering study design, which
has generated considerable national interest and other
centres are now using this innovative design for further
studies based on the initial idea developed by Dr Saunders,”
explains Professor Illidge.
A potentially exciting development for Manchester and the
UK will be the implementation of proton therapy. The
potential benefit of proton therapy over standard radiation
techniques is that the pattern of radiation can be more
readily conformed to the tumour itself thus allowing higher
doses of radiation to be used to control and manage the
cancer while minimising off-target irradiation to healthy
tissue. Manchester has been selected by the Department of
Health as one of only two sites nationally to submit a
business case for the installation of a proton therapy facility.
This exciting development was secondary to the
considerable amount of ground work undertaken by The
Christie and members of the RRR group led by Drs Nick
Slevin, Ranald MacKay and Ed Smith. In addition, a
collaboration has been established between Professor Steve
Hahn's Proton Therapy Group at the University of
Pennsylvania, USA, to share research findings and
experience in order to optimise administration of proton
therapy.
The growing recognition of the strength of RRR within the
MCRC partnership reflects the commitment of MCRC
researchers. Professor Catharine West who leads the
Translational Radiobiology Group within the University’s
10
Manchester Cancer Research Centre - Progress Report
11
Manchester Cancer Research Centre - Progress Report
School of Cancer and Enabling Sciences, has established a
Radiogenomics Consortium that held its first meeting in
Manchester in November 2009. Following the success of
this meeting, the second consortium meeting is due to be
held in the USA later this year. The past year has been
outstanding for Dr Faivre-Finn who along with colleagues
published an important article in the Journal of Clinical
Oncology entitled ’Improving Survival with Thoracic
Radiotherapy in Patients with Small Cell Lung Cancer. The
CONVERT and the REST Trials’. In addition, Dr Faivre-Finn has
been awarded a Clinical Excellence Award, a national
Department of Health award that aims to recognise
exceptional individual contributions. “The number of
Clinical Excellence Awards handed out nationally in 2010
has been halved, with only 317 national awards given to
senior doctors in England and Wales – this is a well-
deserved tribute to a highly committed clinician and
researcher,” said Professor Illidge.
The multidisciplinary ManchesterCancer Research Centre (MCRC) LungCancer Research Group was set up totackle lung cancer and provideimproved treatment options forpatients.
Since its establishment, the Lung Cancer Research Group
has made significant progress through strategic
identification of priority areas to focus co-ordinated
research efforts that drive enhanced patient care.
The Lung Cancer Research Group includes scientists, nurses
and clinicians located at The Christie NHS Foundation Trust,
Paterson Institute for Cancer Research, University Hospital
of South Manchester NHS Foundation Trust (UHSM), North
West Lung Centre (NWLC) and The University of
Manchester. The Group’s research portfolio centres on the
development of new therapies for treatment and has a
major emphasis on discovery and application of novel
biomarkers for early detection of disease and the
development of personalised therapy.
Two priority areas identified by the Group was the need to
provide more support for early detection studies and to
improve tissue acquisition for translational research. “The
last year has seen investment in state of the art endoscopy
equipment to support ongoing and planned longitudinal
studies in which populations at high risk of lung cancer will
undergo surveillance to include serial biopsy of
preneoplastic or neoplastic lesions. Recruitment to
LUNGSEARCH, the first national trial of lung cancer
screening, and a bimodality surveillance study of patients at
high risk of relapse are underway,” said Dr Fiona Blackhall, a
lung cancer specialist at the MCRC and The Christie. In
addition, the number of lung samples banked in the MCRC
Biobank at UHSM now exceeds 200 and bronchoscopy
specimens are also to be collected from October 2010.
Tissue microarrays in squamous cell and small cell
carcinoma are under construction as a resource for
translational and basic scientists for novel target and
biomarker evaluation.
Translational research has also been strengthened with the
award of a clinical lectureship to explore plasma proteomics
signatures in early stage non-small cell lung cancer patients
that may be relevant to future early detection of disease.
“Blood plasma contains a wide range of proteins some of
which may be proteins that are generated during processes
such as cell death. In disease processes such as cancer
development, the composition or profile of the proteins
carried within the plasma can be altered. By studying and
defining protein profiles, the proteomics signature, in
cancerous tissue, we can identify specific signatures that
represent potential markers of disease,” explained Dr
Blackhall. The first clinical proteomics studies of serial
blood samples (CHEMORES European Framework 6 funded
project) from patients with advanced disease are now
underway. At the Paterson Institute the lung focus group in
Clinical and Experimental Pharmacology is leading the field
in circulating tumour cell (CTC) detection and the
application of CTCs for improved understanding of the
biology of tumours. CTC’s are also being evaluated to assess
whether they have pharmacodynamic utility in clinical trials
and if they can be used to monitor the effect of anti-cancer
therapies on the body.
This year the translational portfolio has extended to include
radiation-related biomarkers with the award of a clinical
lectureship and a clinical fellowship. Lung Cancer Research
Group researchers are studying preclinical lung cancer
models of novel drug/radiation combinations. The
radiotherapy focus continues to grow with an emphasis on
evaluating novel treatments in combination with radiation
therapy. A phase I study of the MEK Inhibitor, AZD6244, in
combination with thoracic radiotherapy is ongoing, while
the RADAR study is assessing circulating, tissue and
imaging biomarkers for prediction of radiation response
and/or toxicity. The Manchester-led multinational phase III
CONVERT trial, which aims to identify the optimal total
Progress in Meeting the Lung CancerChallenge
12
Manchester Cancer Research Centre - Progress Report
Manchester Cancer Research Centre - Progress Report
13
dose of radiotherapy to prescribe for small cell lung cancer
and the most effective way of giving radiotherapy
(comparing delivery once versus twice daily), is also
ongoing. In addition, the phase II CONCEPT trial, which is
investigating concurrent chemo-radiotherapy followed by
consolidation chemotherapy in patients with stage II and III
non-small cell lung cancer, will soon close having reached
its target accrual.
In terms of clinical trials, this year Manchester has risen to
be the top recruiting network for National Cancer Research
Network trials due to the combined efforts of the team.
“Through international collaboration the Group has made
major contributions in phase II and III trials of second
generation epidermal growth factor receptor inhibitors and
ALK inhibitors. Gefitinib became the first licensed
treatment for lung cancer where evidence of EGFR gene
mutation is mandatory for prescription,” said Dr Blackhall.
“We are now leading a Europe-wide initiative in external
quality assurance for EGFR mutation analysis through
collaboration with colleagues at the National Genetics
Reference Laboratory, St Marys Hospital and several other
international groups.”
Research towards enhancing patient treatment also
includes identification of methods to improve supportive
and palliative care. A new initiative that brings together
expertise from established research programmes at The
University of Manchester and UHSM has resulted in award
of an NIHR PhD studentship for a clinical fellow and is
focusing on the measurement and management of cough
in patients with lung cancer. “We set out clear objectives
for the Lung Cancer Research Group and have made
encouraging progress in key areas – early detection, tissue
banking, translational research, radiotherapy research and
clinical trials, and supportive and palliative care. These
achievements demonstrate the strength of collaboration
and teamwork in delivering tangible results and the value
of a partnership approach to research that is at the core of
the Lung Cancer Research Group’s and the MCRC’s strategy,”
said Dr Blackhall.
Manchester Cancer Research Centre - Progress Report
14
This September saw the first intake ofMRes students into the MCRC via a newprogramme that providespostgraduate-level training and equipsmedical students with the specialistknowledge and research skills to pursuea research career in oncology.
The MRes in Oncology has been designed as a practical
programme with a focus on clinically relevant skills as
Professor Catharine West, Postgraduate Director at The
University of Manchester’s School of Cancer and Enabling
Sciences explains: “Our aim is to stimulate the best medical
students to become interested in oncology. We want to fire
their enthusiasm for cancer research in order to generate a
critical mass of high-quality clinical, medical and surgical
oncologists who will drive progress in future cancer
research.” The one-year full time course accepted
applications from undergraduate medical students who
had completed year 4 of their degree. The MRes course
combines opportunities to hone practical laboratory skills
together with tutorials and lectures. “Our MRes students
will be getting the most up to date information on cancer,
its progress and latest treatments - a real benefit is that
lectures and tutorials are delivered by internationally
renowned researchers and clinicians drawing on the
expertise that exists across the MCRC partnership to
provide an exceptional learning opportunity,” said
Professor West.
The students also gain 35 weeks of practical experience
through two research placements during the year-long
course. Around 20 diverse projects have been offered and
students are able to choose one which best matches their
interests and may also approach other potential supervisors
within the MCRC if they have a particular area of research
they wish to explore. This year’s intake of four students will
grow as the course matures to a maximum of 18-20
students per year in order to maintain a high calibre of
participants. “The MCRC MRes in Oncology aims to be
flexible so that students can tailor relevant elements of the
course to suit their individual interests. It provides students
the skills and academic training that will help develop
academic oncology leaders of the future,” Professor West
concluded.
Term Starts for MRes Oncology Students
The MCRC Biobank, a regional facilitythat stores biological samples forresearch use and is located at thePaterson Institute for Cancer Research,was established in March 2008 and isproving a valuable resource for theresearch community it supports.
In the past 12 months the repository of biological material
has more than doubled and currently provides secure
storage for over 1,300 patient samples, with around 60 new
samples being added every month. These figures indicate
that the process for collection from the five NHS Trusts
involved in the Biobank collaboration is efficient and
effective. So far, the Biobank has received 24 applications
for sample provision to be used in academic research, 17 of
which have been approved. When applications are received
they undergo a peer-review process by three scientists or
clinicians, including at least one expert in the applicant’s
proposed field of research. Each reviewer gives the project
application a score; these scores are then totalled and
passed on to the Biobank’s Access Subgroup, which is
composed of members of the Management Board. “The
Subgroup reviews the scores and provides final adjudication
based on scientific quality. They also ensure that those
involved in the logistics of sample provision are adequately
consulted so that the Biobank can be sure it is able to
deliver the quality and quantity of material required within
the proposed timescales,” explains Professor Noel Clarke,
Director of the MCRC Biobank. The legal and ethical
implications of the research proposal are also considered
and assessed for compliance. Experience with research
projects over the year have demonstrated that the Biobank
is a flexible resource able to respond to changes in project
needs as the research progresses.
So far, the majority of sample requests have been for
sections from blocks as well as blood and bone marrow
samples, although recently frozen tissue has also been
released. Pathology projects to mine the pathology archive
are also about to start. This will expand the tissue
repository and will link tissue samples to patient databases
whose clinical outcomes have been documented over time,
which will be a particularly valuable resource. To facilitate
this there is now an expanded team of seven technicians
collecting samples, including two specialists. One is a lung
specialist technician funded by AstraZeneca through the
MCRC/AZ Alliance and is based at Wythenshawe Hospital,
part of University Hospital of South Manchester NHS
Foundation Trust, and the other is a specialist in male
cancers funded by the Men Matter charity and is based at
Salford Royal NHS Foundation Trust and The Christie.
To enable better information and access for users to the
system, the Laboratory Information Management System
(LIMS) database was purchased and installed six months
ago. This is now up and running, with sample data being
routinely logged on the system. Following this test phase
the LIM System will be further customised by an in-house
informatics analyst to ensure it services the needs of the
Biobank. “The next step is to provide secure remote access
to LIMS so that technicians based at the collecting Trusts
are able to enter and retrieve information from their own
hospital. This should make the process simpler and more
efficient, helping the Biobank provide a professional service
to the research community,” said Professor Clarke.
MCRC Biobank Continues to Develop andExpand
Manchester Cancer Research Centre - Progress Report
15
Spring Marked Launch of Breast CancerResearch UnitThe Breakthrough Breast CancerResearch Unit was officially launchedon 4 March 2010 and has alreadydeveloped a coherent research strategyfor the Unit focusing not on cancer cellsthemselves but on the cells andmaterial which surround the tumourcells.
Professor Tony Howell, Director of the Breakthrough Unit
explains the rationale behind the strategy: “Most breast
cancers originate from previously normal breast epithelial
cells but in normal breast tissue, epithelial cells account for
only around 10% of all the cells that make up the breast.
The remaining 90% is stroma - an elaborate mixture that
includes blood vessels, fat cells, immune cells and a range of
connective tissue cells. There is increasing evidence that
although not innately cancerous, stromal cells play a pivotal
role in the development and progression of cancer.”
By taking this relatively novel approach, Breakthrough
researchers aim to answer several key questions in breast
cancer. Firstly, whether it is possible to identify stromal
factors that predict risk of breast cancer and therefore to
focus preventative measures to high-risk groups. Secondly,
whether stromal factors can be used to predict the
likelihood of cancer spread or metastases and also
sensitivity to treatment. Four Team Leaders have now been
appointed to the Unit to drive the overarching research
strategy: molecular pathologist Professor Goran Landberg,
cancer cell biologist Professor Michael Lisanti,
developmental biologist Dr Paul Lu, and stem cell biologist
Dr Robert Clarke. Clinical associates Professor Howell,
Professor Nigel Bundred and Dr Sacha Howell, provide
clinical leadership for the strategy.
The potential relationship between stromal factors and risk
of breast cancer is being explored and already data from
Professor Landberg’s team suggest that the presence of
cross-linked collagen in normal breast is associated with a
higher risk of breast cancer development. Based on these
and other supportive data the next steps are to elucidate
the mechanisms of stroma-cancer cell interactions, to
search for stromal markers of risk and to test the utility and
validity of these markers in clinical studies. Other data
within the Unit indicate that the stroma is intimately
involved in the progression from localised disease to
invasive disease and that the stroma indicates metastasis
and resistance to treatment. This will be further explored
within the Unit by focusing on the identification of stromal
markers during tumour evolution, metastases and
development of resistance and also by undertaking studies
to better understand the mechanisms of action that
underpin these processes.
“A final question we want to answer is whether the use of
therapies directed at stromal elements, rather than the
conventional target of the tumour cell itself, could improve
patient response to treatment and outcome. It may be that
we can identify stromal targets able to reverse resistance to
standard therapy and thereby provide a more effective
combination approach. However, it may be that stromal
targeted therapy has the potential to become the main
therapy option and not an add-on – at this stage we don’t
have the answers. By working together in a considered and
rational approach to key challenges we are ideally placed to
have an impact on outcomes for breast cancer patients,”
said Professor Howell.
Manchester Cancer Research Centre - Progress Report
16
17
Manchester Cancer Research Centre - Progress Report
MCRC Gains Centre Status
The Manchester Cancer Research Centre(MCRC) was officially accredited as aCancer Research UK (CR-UK) Centre inApril 2010, one of around 20 Centres tobe accredited by the end of 2010.
The accreditation is further and formal endorsement of the
collaborative strategy for research that is at the heart of the
MCRC’s approach to optimising the use of scientists,
clinicians, facilities and resource in order to drive innovative
and clinically-relevant research in cancer.
The Centres initiative is a major part of CR-UK’s five-year
research strategy and one of its highest priority strategic
programmes, the aim of which is to develop long-term,
sustainable Centres of excellence in cancer, delivering world-
class research, improved patient care and greater local
engagement. It was modelled on the partnership working in
Manchester within the MCRC and aims to promote close
collaboration between organisations that have a shared goal
of improving treatments for cancer patients. As a
partnership between academia (The University of
Manchester, which includes the Paterson Institute for Cancer
Research which is core-funded by CR-UK), the NHS (The
Christie NHS Foundation Trust) and the charitable sector
(CR-UK), the success of the MCRC since its establishment in
January 2006, provides tangible proof of the benefits that
can be achieved through partnership and that are the driving
force behind CR-UK’s Centres initiative.
The MCRC’s first fellowship fundedthrough the Singaporean StrategicAttachment and Training (STRAT)scheme ended this summer and wasjudged a resounding success. Dr Ying-Kiat Zee, from the National UniversityCancer Institute Singapore (NCIS), hasrecently completed a one-yearplacement as a clinical research fellowworking with Professors Gordon Jaysonand Caroline Dive; a placement that wasmutually beneficial.
Professor Jayson explained: “Dr Zee proved himself a superb
clinician and researcher. He was highly motivated to make
the most of his placement and worked extremely hard
throughout the year.” Dr Zee focused on early clinical trials
of novel anti-angiogenic agents that aim to exert an
anticancer effect by targeting angiogenesis, the formation of
new blood vessels upon which tumours rely for growth.
As well as participating in phase I clinical trials, Dr Zee gained
valuable imaging experience and made a very positive
contribution to the research team. He wrote reviews for
Nature and an ethics paper and continues to be involved
with the Translational Angiogenesis research group within
the University’s School of Cancer and Enabling Sciences. “Dr
Zee is currently working with us in a joint project analysing
metabolomics data, characterising the small molecule
metabolites generated as a result of anti-cancer treatment,
and has set up two clinical trials with the MCRC and another
in Singapore,” said Professor Jayson. One of the two
collaborative trials focuses on the development and
validation of assays to identify mutations in circulating DNA
and the other on characterisation of circulating endothelial
cells, the cells which form the inner lining of tumour blood
vessels, in patients undergoing different chemotherapy
treatments. “The aim of these studies is to see if we can
identify biomarkers that reflect damage to tumour blood
vessels. Once validated, these biomarkers can be used to test
the activity of future anti-angiogenic agents,” explained
Professor Jayson. “The STRAT placement has been a real
benefit to our group and also to Dr Zee and could lead to a
lasting research relationship between the MCRC and Dr Zee’s
team.”
18
Manchester Cancer Research Centre - Progress Report
STRAT Fellowship Success
19
Manchester Cancer Research Centre - Progress Report
Fulfilling the long-term strategy of theManchester Cancer Research Centre(MCRC) will require an increase inresearch activity and capability, togetherwith increased investment in new areasof research and continued recruitment.
“In particular, there is a growing emphasis on personalised
medicine where treatments are selected based on improved
knowledge of a patient’s disease characteristics. We are
almost at full capacity with existing research space and in
order for the MCRC to reach its full potential, we need to
provide a state-of-the-art environment where research can
flourish,” said MCRC Director,
Professor Nic Jones.
Following discussion and agreement with MCRC partners, a
significant investment of £20 million has been secured for
the development of a new laboratory research building.
Cancer Research UK is providing £10 million towards the new
build with an additional £10 million from The University of
Manchester and land being provided by The Christie NHS
Foundation Trust. With funding now in place, the next year
will focus on the planning and design element of the build
taking into account end-user needs to ensure that the new
building has the space and facilities to support high quality
research. “The new laboratories will be used to expand
current cancer research activities, develop new strategic
initiatives and continue to develop excellent research
infrastructure. The development will ensure that we have a
facility able to support the progress and growth that
underpins future achievements,” said Professor Jones.
Building for the Future
Manchester Cancer Research CentreThe University of ManchesterWilmslow RoadManchesterM20 4BX
tel: 0161 446 3156fax: 0161 446 3109email: [email protected]
www.manchester.ac.uk/mcrc