Manchester Cancer Research Centre · 2013-10-17 · aberrations in this communication process can lead to the development of cancer. Dr Lu’s research focuses on understanding the

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


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.


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.


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.


6

Patient Treatment Centre Triples Spacefor Early Clinical Trials


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


MCRC Imaging Group: ResearchMotivated by Reality


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


11


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



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.


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


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.


16

17


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


STRAT Fellowship Success

19


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

Documents

Manchester Cancer Research Centre · 2013-10-17 · aberrations in this communication process can lead to the development of cancer. Dr Lu’s research focuses on understanding the