Manchester Cancer Research Centre Research Report 2013/14 Researc… · Welcome to the 2013-14...

Manchester Cancer Research Centre Research Report 2013/14

Manchester Cancer Research Centre Research Report 2013-14

Manchester Cancer Research CentreThe University of ManchesterWilmslow RoadManchester M20 4BXTel: +44 (0) 161 446 3156www.manchester.ac.uk/mcrc

Founding Partners:

The University of ManchesterOxford Road Manchester M13 9PL Tel: +44 (0) 161 306 6000www.manchester.ac.uk

The Christie NHS Foundation TrustWilmslow RoadManchesterM20 4BX Tel: 0845 226 3000www.christie.nhs.uk

Cancer Research UK Angel Building407 St John StreetLondonEC1V 4ADTel: +44 (0) 20 7242 0200www.cancerresearchuk.org

Copyright © Manchester Cancer Research Centre

M a n c h e s t e r C a n c e r R e s e a r c h C e n t r e R e s e a r c h R e p o r t 2 0 1 3 / 1 4 3

ContentsRe

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Chair’s Foreword 4 Introduction 5

Ambitious plans for 8 Experimental Therapeutics Andrew Hughes, Jonathan Tugwood, Caroline Dive, Matt Krebs, Emma Dean

Breast Cancer research at the 14 Manchester Breast Centre Tony Howell, Rob Clarke, Gareth Evans

Circulating tumour cell (CTC) research 18 in early stage, resectable non-small cell lung cancer (NSCLC) Caroline Dive, Fiona Blackhall, Phil Crosbie, Rajesh Shah

Heterogeneity in Melanoma 24 Claudia Wellbrock

Translating Cancer Biology into 26 Novel Therapeutics Allan Jordan, Ian Waddell and Donald Ogilvie

Collaboration pays dividends for 32 Leukaemia research Tim Somervaille

Ovarian cancer and angiogenesis 34 Gordon Jayson

Key role for Radiotherapy in 38 personalised approach to cancer treatment Tim Illidge, Catharine West and Nick Slevin

Imaging Science research at the MCRC 42 JamesO’Connor,AdamMcMahon,GeoffParker,

Kaye Williams and Alan Jackson

Biobank building on success 48 Jane Rogan

Author Biographies 54

M a n c h e s t e r C a n c e r R e s e a r c h C e n t r e R e s e a r c h R e p o r t 2 0 1 3 / 1 44

Chair’s ForewordWelcome to the 2013-14 Biannual Research Report of the Manchester Cancer

Research Centre (MCRC).

The research work at the MCRC lies at the heart of cancer care not only in

Manchester but both nationally and internationally. Once again we continue to

see great strides forward in all aspects of our work.

The Research Report is a snapshot of some of the impressive progress that has

been made at the MCRC during 2013 and 2014, in terms of both growth and

research output. Even a quick glance at the Report is enough to see that our

scientistsandclinicianscontinuetobepioneersintheirfield,providinginnovative

approaches to the diagnosis and treatment of cancer as well as increasing our

fundamental understanding of the disease at a cellular level.

The work we undertake in the MCRC makes us not only a national beacon of

excellence in cancer research but highlights the fact that we are an internationally

networked Centre that puts into practice our vision of precision medicine.

The last two years have been very successful for the Centre. The MCRC

received renewed and expanded centre status from Cancer Research UK which

will enable us to implement an ambitious plan for further growth, including the

development of a Centre for Biomarker Sciences. This new centre will provide

state-of-the-art facilities for researchers and clinicians, enabling them to

accelerate biomarker sciences and research and bring about a future where

all cancer treatment is tailored to individual patients. New facilities are being

planned that will complement the iconic new MCRC building that is nearing

completion on our Withington site.

The arrival of formidable world-leading researchers has strengthened expertise

within key research areas and enables us to maximise the opportunities we have

in proton therapy and image-guided radiotherapy research. Collaborations and

networkingarekey tosuccessful scientificendeavourandMCRCresearchers

have played their part by driving the development of Centres of Excellence in

Lung Cancer with UCL in London, Prostate Cancer with Queens University,

Belfast and Cancer Imaging with the University of Cambridge. The creation of

these Centres really does recognise the diverse contributions that Manchester

makes across the full cancer research spectrum.

Looking to the future, we are committed to delivering on our promise. We have

anunrivalledopportunityinManchestertoofferlifesavinghopeforpatientswith

cancer by matching the right treatment to the right patient. We aim to become

not just a national beacon of excellence in cancer research, but an internationally

networked centre, and put into practice our vision of precision medicine.

Michael Oglesby

Chair

Manchester Cancer Research Centre

Michael OglesbyChairManchester Cancer Research Centre


IntroductionThe vision of the MCRC is one of precision medicine, where each cancer patient

receives the right treatment at the right time, tailored to his or her individual tumour.

Our aim therefore is to better understand the cellular processes and mechanisms

that drive cancer initiation and growth, in order to identify potential targets for

therapeutics, to develop such novel agents and to evaluate new treatment

approaches in the clinic. This report highlights some key research areas that

are contributing to the discovery and implementation of more personalised

cancer treatments.

Vital to our vision is the Experimental Cancer Medicine team, based at The

Christie’s Clinical Trials Unit. The article by Andrew Hughes and collaborators from

the Clinical and Experimental Pharmacology group highlights the successes of

the Unit and the strengths of Manchester as a location for Experimental Cancer

Medicine research. By having early phase trials co-located on our Withington

site with a wealth of biomarker science expertise, we really are in a position to

drive forward biomarker-driven trials of novel agents. The ambition of Andrew

and his team is formidable, and recent progress gives indications of an exciting

future for Experimental Cancer Medicine at the MCRC.

The Manchester Breast Centre is an important part of the MCRC and its groups

continue to work on various aspects of breast cancer research. The report

by Tony Howell, Gareth Evans and Rob Clarke summarises how their recent

laboratory discoveries relate to the current concept of normal breast biology

and describes clinical studies looking at the prediction and prevention of breast

cancer risk.

Lung cancer is a priority area for the MCRC, and in 2014 we became a Cancer

Research UK Lung Cancer Centre of Excellence, in conjunction with colleagues

at UCL. Earlier diagnosis is key to improving survival rates in this disease, but

we also need to better understand the process of metastasis. The report from

the Lung Cancer group details progress being made in two studies that hope

to improve our understanding of the molecular mechanisms behind metastasis.

Professor Nic JonesDirectorManchester Cancer Research Centre


Their work is focusing on the potential of circulating tumour cells (CTCs) to provide information on metastatic

behaviour in early stage non-small cell lung cancer (NSCLC). The impressive development of CTC-derived

explant models using CTCs taken from small cell lung cancer (SCLC) patients has now been replicated in

NSCLC and this pioneering approach can hopefully be used to predict risk of disease recurrence.

As in other cancer types, genetic and phenotypic heterogeneity within melanoma must be considered when

developing and applying therapeutic approaches. The report by Claudia Wellbrock summarises her laboratory’s

work looking at cellular subpopulations that contribute to both treatment response and invasion. The group

found, in separate studies, that the factors MITF and TNFα both play a role in treatment resistance and in a

fascinating experiment involving zebrafish, the researchers showed that heterogeneous melanoma cells

worked cooperatively in order to invade surrounding tissue.

A real strength of the MCRC is the experience and facilities within the Drug Discovery Unit, allowing us to

translatelaboratoryfindingsfromourresearchgroupsintopotentialnewsmall-moleculecancertherapeutics.

The report from Donald Ogilvie, Allan Jordan and Ian Waddell focuses on two projects that have seen great

progress over the last two years – those looking at the development of PARG and RET inhibitors.

Collaboration is key to successful research, and a joint project between our drug development team and

clinician scientist Tim Somervaille has resulted in an exciting development in Haemato-oncology. Tim’s

article highlights work exploring the potential of LSD1 inhibition for the treatment of acute leukaemia – early

laboratory work by the Leukaemia Biology group and the Drug Discovery Unit has led to a collaboration with

Oryzon Genomics, a Spanish biotech company, on a phase I clinical trial.

Manchester Cancer Research Centre Research Report


Identifying the hallmarks of cancer is one route to developing new anti-cancer treatments. In the search for

novel targets in ovarian cancer, angiogenesis is the focus for Gordon Jayson and his group. His report details

recent experiments by his group exploring the role played by heparan sulphate in regulating angiogenesis-

related growth factors.

The role of radiotherapy in more personalised treatment approaches must not be forgotten. Indeed, the article

from the Radiotherapy Related Research group summarises work done by Catharine West to investigate

potential biomarkers to predict radiosensitivity, radiotherapy-related toxicity and benefit from hypoxia

modifying agents. In addition, Tim Illidge reports results from several studies using novel immunomodulatory

agentstoincreasetheeffectofionisingradiation.

Our expertise in cancer imaging was recognised in 2013 with the award of a CRUK-EPSRC Cancer Imaging

Centre, in conjunction with Cambridge. Since then, good progress has been made. The article from some

of the Centre’s leading investigators highlights success across a wide portfolio of projects, including the

development of a ‘roadmap’ for the validation of imaging biomarkers.

Following its creation in 2007, the MCRC Biobank has supported research across the Centre through the

collection and provision of high quality patient samples. The report from Jane Rogan and Noel Clarke details

howtheirflexibleapproachtobiobankinghasfacilitatedavarietyofstudiesandenabledManchestertomakea

significantcontributiontonationalresearchinitiatives.

We are entering a new era of cancer research in Manchester and, thanks to the impressive progress over

the last two years, are well placed to deliver on our vision of a personalised approach to treatment for all

cancer patients.

Professor Nic Jones

Director

Manchester Cancer Research Centre

Introduction



Andrew Hughes, Jonathan Tugwood, Caroline Dive, Matt Krebs, Emma Dean

Ambitious plans for Experimental Therapeutics

Experimental Medicine was defined as one of three core themes

alongside Radiation-Related Research and Lung Cancer in the successful

2008 Manchester Cancer Research Centre (MCRC) Cancer Research UK

Centre application.

This facilitated the MCRC to develop a 2000m2 state-of-the-art Clinical Trials

Unit comprising 31 beds/treatment chairs, 6 inpatient beds, 5 outpatient suites

and a large sample collection laboratory. The Unit has supported 66 Phase I

and 183 Phase II clinical trials, involving 3,202 patients in experimental studies

since its opening in 2010. It was ranked as a ‘forefront’ UK Experimental Cancer

Medicine Centre (ECMC), recruiting 25% of all UK patients into ECMC clinical

trials from the largest catchment population (3.2M people) for a cancer centre

in England and Wales with over 14,000 new patients/annum. The Clinical Trials

Unit was built with the aim that it would become one of the largest centres

for experimental cancer medicine trials worldwide. We remain committed to

this target, which will provide clear evidence that The Christie and the broader

MCRC is a leading cancer centre.

The Experimental Cancer Medicine team, located within the Clinical Trials

Unit, conducts early phase clinical trials comprising first-in-human and first-

in-combination studies with the objective of providing a recommended dose

and schedule for further (Phase II) testing. The Experimental Cancer Medicine

team also conduct ‘Regulatory Clinical Pharmacology’ trials. These trials often

comprise the majority of text in the drug prescribing information and the

majority of clinical study reports in a submission dossier. These studies seek to

characterise the impact of food (food interaction studies), organ impairment

(renal and hepatic studies), concomitant medication (drug-drug interaction

studies), formulation changes (bioequivalence and bioavailability studies)

upon the exposure (pharmacokinetics) of the drug; and characterisation of

absorption, distribution, metabolism, elimination (ADME) of the drug.

The Experimental Cancer Medicine team within the Clinical Trials Unit is

ideally located next to the cancer discovery and translational laboratories

within the Cancer Research UK Manchester Institute (CRUK MI). Other key

translational platforms have also been developed within the MCRC including (i)


Ambitious plans for Experimental Therapeutics

The Wolfson Molecular Imaging Centre, which together with colleagues from

Cambridge recently attained CRUK-EPSRC Cancer Imaging Centre status and

is well equipped to deliver imaging biomarkers for application in experimental

therapeutics cancer clinical studies (PET, MRI, CT, MRS); (ii) Clinical and

Experimental Pharmacology (CEP) laboratories - one of the best laboratories

world-wide in cancer biomarker discovery, validation and development within

the CRUK MI (iii) an extensive and successful biobanking infrastructure that

can capitalise on the very high patient population. Planned delivery of an

Integrated Procedures Unit from 2016 will further augment the ability to deliver

translational clinical studies, with the provision of radiology guided biopsies

and procedures for bone marrow aspiration and surgical biopsies (breast, skin,

melanoma, sarcoma, renal, prostate, bladder, cervix, endometrium, ovarian,

vulval, vaginal, colorectal, anal, and peritoneal).

We now have an enormous opportunity to be a major international centre

for experimental cancer medicine providing access to novel therapies for

a significant proportion of patients. We aim to become a ‘go-to’ centre for

scientificallydrivenandbiomarkerinformedtrials,tobeamagnetforworld-class

staff,tobeatrainingbeaconinexperimentaltherapeutics,andbyimplementing

the biomarker expertise from CEP in the clinic, to become a leader in ‘liquid

biopsy’ precision medicine with real-time clinical trial data acquisition that

enables adaptive decision making in Phase I trials and to work in partnership

with other centres to conduct basket/bucket trials.


Ourgoaloverthenext fewyears istofully realisethisopportunity: tobefirmlyestablished inthetopthree

UnitsinEuropewithinthenextfiveyearsandinthetopfivegloballywithinthenexttenyears.Thiswillrequire

a5-10foldincreaseinthenumberofearlyphasetrialsoverthenextfiveyearsanda10-20foldgrowthover

the next ten years in the number of patients enrolled into such trials; and in the overall scale of operations,

without compromising the high quality of patient care currently delivered. Our long-term global aspiration will

requireevenfurtherinvestmentandtheestablishmentofeffectiveandintegratednetworkswithothermajor

therapeutic units especially in the UK.

Wehavetakenourfirsttangiblegrowthsteps.InJuly,twoseniorlecturers-DrMattKrebsandDrSaeedRafii-

were appointed alongside Dr Emma Dean, who was appointed as Senior Lecturer in the experimental cancer

medicines team in 2012. Emma has pursued postgraduate study in human pharmacology and together with

ProfessorMalcolm Ranson, who retired earlier in 2014, has administered over 170 different experimental

cancer medicines since 2007. Dr Matt Krebs undertook his PhD in circulating biomarkers in CEP and his research

interestisinnon-smallcell lungcancer.DrSaeedRafiijoinedusfromtheRoyalMarsdenHospital,whichhas

a thriving experimental cancer medicine team within the Drug Development Unit that enrols 300-400 new

patients into experimental cancer medicine studies each year. Saeed’s insights into running a department

of this scale will be invaluable as we scale up. From April 2015, Professor Andrew Hughes will be joining the

experimental cancer medicine team as Strategic Director to drive investment and growth. Andrew has held a

joint appointment with The University of Manchester as Chair in Experimental Therapeutics since 2008 and

has been vice-president for early oncology clinical development within AstraZeneca. Andrew has commenced

workwiththeExperimentalCancerMedicineteamtodefinethetrajectoryforgrowthandinvestment.



Sincetheirappointments,SaeedRafii,MattKrebsandEmmaDeanhavebroughtsevennewtrialstopatients

includinganovelATR inhibitor,withTheChristieenrollingthefirstUKpatienttothefirst-in-humanstudy in

November 2014. Other agents include a TOR1/2 inhibitor and a tyrosine kinase inhibitor which not only

inhibits theEGFRmutated receptor (as thefirstgenerationEGFR-TKIssuchas IressaandTarceva)but the

resistance mutation (T790) which develops in some 50% of patients with non-small cell lung cancer. The orally

administered drug is set to submit its registration dossier in 2015 with the experimental cancer medicines

unit conducting three regulatory clinical pharmacology studies to support this submission. Discussions are

ongoing with sponsors for a further seven trials.

In addition to increasing the number of new experimental cancer medicines reaching patients, the

experimental cancer medicine team, working closely with CEP, has also commenced work to build a ‘liquid

biopsy precision medicine’ capability. This maps to the research themes of the CRUK MI and the University’s

Institute of Cancer Sciences. Several major cancer centres across the world are routinely performing DNA

sequencingontheirpatients’tumourtissuetoinformtreatmentstratification-tryingtomatchtheobserved

molecular aberration to a targeted therapy. Recognising that we are behind other cancer centres, we have

electedto focusuponestablishingtheclinical researchcapability formultiplexmolecularprofilingonblood borne tumour derived material (circulating tumour cells (CTCs) and circulating tumour DNA (ctDNA)). Patients

will therefore simply need to provide a blood sample (a ‘liquid’ or virtual biopsy) rather than having to undergo

a tumour tissue biopsy with associated morbidity and mortality. Already treatment decisions are being made

uponthemolecularaberrationsfound inctDNA. InSeptember2014, Iressa-firstdosedtopatients inThe

Christie by Professor Ranson - received approval from the EU licensing authorities, meaning that patients with

non-smallcelllungcancercanbetreatedwithIressauponfindingaEGFRmutationinctDNAwithouthaving

to proceed to a tumour biopsy. The ability to characterise the molecular phenotype of a cancer based upon a

‘liquid biopsy’ will be a critical element in repositioning experimental cancer medicine from being considered

only after all standard of care options have been exhausted (and thus typically an end-of-life experience for

patients) to being considered earlier in the treatment pathway when drugs available under an expanded clinical

trialsportfoliocanbematchedtoputativetumourmoleculardrivers identifiedthroughmultiplexmolecular

profilingfromabloodsample.

The Manchester Cancer Research Centre Conference: Harnessing Apoptosis



The experimental cancer medicine team has now developed a clinical protocol to allow DNA sequencing for

all patients being considered for an early phase clinical trial, aiming to match relevant experimental agents

with individual genetic aberrations. The clinical trial, known as TARGET (Tumour chARacterisation to Guide

Experimental Targetedtherapy), isduetoenrol itsfirstpatient inearly2015.Thepatientconsentformand

patient information sheet were recently recognised by Independent Cancer Patients’ Voice as exemplars in

theirfield.WehavealsosetupasteeringboardforthisprojectcomposedofMCRCmultidisciplinaryexpertise,

inclusive of The Christie NHS Foundation Trust Research and Development team, the University’s Institute

of Cancer Sciences and CRUK MI clinical and translational scientists, the regional genetics laboratories at

St Mary’s within Central Manchester University Hospitals NHS Foundation Trust, and linked to the ongoing

Integrated Procedures Unit project development.

Samples from this TARGET precision medicine clinical trial will be sent to the CEP laboratories for analysis. The

CEP group, headed by Professor Caroline Dive, comprises over 50 scientists and includes teams dedicated to

high quality non-clinical mechanistic cancer research, the development and implementation of nucleic acid

biomarkers, and a team dedicated to the characterisation of circulating biomarkers in ‘liquid biopsy’ samples

from clinical trials and experimental medicine projects, under Good Clinical Practice (GCP) standards and

regulations. Analysis of clinical trials samples to GCP involves teams of project managers, laboratory-based

analysts and a dedicated Quality Assurance group to oversee GCP compliance. CEP currently has 60 clinical trial

and experimental medicine projects in its portfolio, with another 13 currently in the planning stage. The portfolio

focuses on major cancer disease areas with emphasis on lung, melanoma, colorectal, pancreatic and prostate;

sponsorship and funding includes collaborative relationships with seven major international pharmaceutical

companies, UK NHS Hospital Foundation Trusts, UK universities and UK and European research councils.

ThecornerstoneoftheCEPgroup’seffort istheexperimentalcapabilitythatunderpinstheclinicaltrialand

experimental medicine project activity. Importantly, we have a portfolio of 96 biomarker assays validated to

GCP standards, aligned to CTC enumeration and characterisation, protein biomarker analysis by single-plex

andmulti-plexELISA,andgenomicanalysisoftumourbiopsiesandofctDNA.CTCresearch istheflagship

activityofCEP.Wehaveestablishedcapability forCTCenumerationandstainingforspecificmarkersusing

the FDA-approved Veridex CellSearch platform, and also using the Isolation by Size of Epithelial Tumour

Cells (ISET) approach. In addition, to complement existing platforms we are developing several alternative

approaches in collaboration with service provider organisations, to develop the capability to isolate CTCs using

parameters such as cell size, conformation, and isolation of live cells. In conjunction with new CTC isolation

platforms, we are developing the capability to isolate and characterise single CTCs. This is being led by deputy

CEP director Dr Ged Brady and his nucleic acid biomarker team. As well as single CTC isolation using the

DEPArray™ instrument, Ged’s team is optimising techniques for whole genome DNA analysis, plus RNA and

miRNA analysis, from single isolated cells. Preclinical pharmacology in CEP, led by Dr Chris Morrow, has been

developing unique mouse models for lung cancer (termed CDX) based on implantation of isolated CTCs from

patients. This has been highly successful, and the development and early characterisation of these unique CDX

models was the subject of a Nature Medicine publication in June 2014. The models, developed from CTCs from

small cell lung cancer patients, recapitulate patient responses to standard chemotherapy. The CDX models are

now the subject of newly-initiated studies with a number of pharmaceutical companies and academic partners

to assess efficacy of targeted therapies alone and in combinationwith standard of care drugs. Promising

therapies will be translated to early clinical trials in SCLC patients within the CRUK Lung Cancer Centre of

Excellence in collaboration with Dr Fiona Blackhall from Manchester and Dr Martin Forster from UCL.


The Manchester Cancer Research Centre Conference: Harnessing Apoptosis



Tony Howell, Rob Clarke, Gareth Evans

Breast Cancer research at the Manchester Breast Centre

The major aim of the Manchester Breast Centre is to translate discoveries from

the laboratory to the clinic in order to improve breast cancer risk estimation,

treatment and prevention.

The laboratories associated with the MBC are situated in the Paterson building

in Withington and within the Faculty of Life Sciences on the University’s main

campus. Clinical studies and trials occur at The Christie, the Nightingale and

Genesis Prevention Centre at University Hospital of South Manchester and

throughout the Cancer Network.

Breast cancer is thought to arise from a terminal-duct lobular unit (TDLU) in one

of the 10-20 lobes of the breast. Each lobule comprises basal myoepithelial and

luminal cells with their corresponding progenitor/stem cells. Luminal progenitor

cells are thought to be the predominant site of origin of the majority of breast

cancers. Stromal cells includingfibroblasts, fat, immuneand vascular cells lie

outsidetheepithelialbasementmembranebutinfluenceepithelialgrowthand

transformation. Greater understanding of the interaction between cell types

and systemic factors is likely to lead to better treatments and prevention of the

disease. In 2014 the majority of MBC publications related to mammary stroma

and mammographic density, stromal and stem cell signalling and aspects of risk

estimation and prevention of breast cancer.

Mammary stroma and mammographic density

The mammary stroma is the non-fat part of the breast and comprises non

cellular structures; predominantly collagens, proteoglycans and cellular

elements including fibroblasts, immune and vascular cells. During puberty

mammary ducts extend throughout the breast mainly associated with stroma.

The degree of ductal spread and branching is related to density of the breast,

and high mammographic density is a strong risk factor for breast cancer.

Potential control mechanisms for the degree of branching were reported by

researchers from the Wellcome Trust Centre for Cell-matrix Research. The

group demonstrated fibroblast growth factor (FGF) signalling from stromal

cells tobreastepithelialstemcells;firstbranching initiationoccursunderthe

influenceofFGF10andductalelongationthenoccursviathereleaseofFGF2.It

appears that both growth factors signal through FGFR2 receptors on epithelial


cells. The degree of branching is reduced by an epithelial tyrosine kinase called

Sprouty which may be regarded as a tumour suppressor. Thus the FGF-Sprouty

pathway may regulate the degree of branching and this risk of subsequent

breast cancer.

Twin studies indicate that about two thirds of mammographic density is

hereditary. The other third varies in relation to breast cancer risk factors;

late age of first pregnancy andHRT increase densitywhereas it ismarkedly

reduced in some women treated with tamoxifen. Recently Michael Lisanti and

hiscolleaguesdemonstrated,usinggeneexpressionanalysis,thatfibroblasts

derived from high density breasts had some features of pro-inflammatory

cancer associated fibroblasts including the activation of the JNK1 stress

pathwayassociatedwithinflammationandfibrosis.Wehaveshownpreviously

that tamoxifen reduces risk of breast cancer only in the 50% of women who

have a >10% reduction in mammographic density. The discovery of the

importance of the JNK1 pathway suggests inhibitors of this pathway may be

useful for non-responders to tamoxifen. Another indication of altered stromal

interactions was detected in what is thought to be the earliest lesion on the

pathway to breast cancer, columnar cell hyperplasia. In this lesion we showed

upregulation of the miR 132 in the stroma and downregulation of let-7c in the

epithelium. Let-7c is known to reduce ERα and may be one explanation of the

high proportion of ER+ cells in these lesions.

Epithelial stem/progenitor cell signalling

Since tumours are thought to arise from stem/progenitor cells it is important to

further elucidate this mechanism in order to develop new targets for therapy.

Studies by MBC members have given insight into the regulation of normal

epithelial stem/progenitor proliferation, and how this may be disrupted during

the development of ductal carcinoma in-situ and invasive breast cancer. We


Figure: Current concept of the organisation of the normal breast related to MBC discoveries in 2014. Stromal fibroblasts produce factorswhichaffecttheactivityofepithelialcells and may be activated in dense breasts. Basal progenitor cells give rise to myoepithelial (contracting) cells. Luminal progenitors give rise to sensor cells which contain oestrogen (ER) and progesterone (PR) receptors and respond to circulating oestrogen and progesterone respectively. Alveolar progenitors are found in pregnancy and give rise to milk producing and other cells. Recent work indicates thatstromalcellsinfluenceepithelialprogenitors via stromal derived growth factor (SDF-1) interacting with CXCR-4 receptors and stromal fibroblastgrowthfactors(FGF2&10)interacting with FGFR2 receptor on the epithelial progenitors. Progenitors also interact with stromal integrins which activate focal adhesion kinase (FAK) and downstream pathways. It is thought that basal and luminal progenitors arise during development from primordial stem cells.

1. Duct reconstruction to show lobar structure.

2. Breast of 18 year old sectioned.

3. TDLU Terminal Duct-Lobular Unit showing ductules.

4. Electron micrograph of a cross section of a ductule


demonstrated that the cytokine receptor CXCR-4 is up-regulated on progenitor cells of the breast. Treatment

withitsstromalactivator(StromalDerivedFactor1-SDF1)hadadualeffect:therewasdown-regulationof

normal progenitors but up-regulation of tumour cell progenitors, a process which could be inhibited by the

bicyclam CXCR-4 inhibitor, AMD 31000, now in clinical development.

Progenitor cells express integrins which sense components of the mammary stroma. For example α6β4

integrin is the cell surface receptor for stromal laminin. In collaboration with a Portuguese group we have

demonstrated that P-cadherin, responsible for cell-cell adhesion, is up-regulated in basal-like mammary

tumours and, in turn, causes down-regulation of α6β4 integrin, increased tumour cell motility and activation

of down stream focal adhesion kinase (FAK). The activation of P-cadherin may explain the increased invasive

properties of epithelial stem cells observed in response to oestrogen.

Analysis of the proteins regulated in tumour stem cells indicated up-regulation of mitochondrial proteins.

Mitochondria require L-lactate and ketone bodies as fuel substrates which are taken up into the cell by

monocarboxylate transporters.Wehave recently shown that specific inhibitionof lactate transport inhibits

stem cell proliferation in oestrogen receptor positive and negative cell lines and suggests the importance of

inhibitors of MCT, such as AZD 3965, entering clinical development. More recently a separate form of stem/

progenitor cell for alveolar milk producing cells was described, the proliferation of which is, in part, controlled by

the transcription factor RUNX2 and B3 integrin. The relevance of the alveolar stem cell to the development of

human breast cancer remains to be discovered.

We have demonstrated that focal adhesion kinase (FAK) is also up-regulated in the progenitor cells of

aggressive forms of human ductal carcinoma in situ (DCIS) and is predictive for relapse and invasion of this




DCIS subtype. FAK inhibition reduces progenitor cell growth and it is planned to test this inhibitor in the clinic.

Lapatinib also reduces DCIS progenitor cell growth and thus may also be used to prevent relapse in patients

with high risk DCIS. In a collaborative study, the mTOR inhibitor everolimus was shown to be highly active when

combined with endocrine therapy for advanced disease. New inhibitors, hopefully with reduced toxicity, are

being developed which could be used for adjuvant therapy and for prevention of DCIS relapse and possibly for

breast cancer prevention.

Recently, there has been an increasing interest in the development and characterisation of patient-derived

tumour xenograft (PDX) models for cancer research. PDX models mostly retain the principal histologic and

genetic characteristics of their donor tumour and remain stable across passages. These models have been

shown to be predictive of clinical outcomes and are being used for preclinical drug evaluation, biomarker

identification,biologicstudies,andpersonalisedmedicinestrategies.

Risk prediction and prevention of breast cancer

Members of the MBC published an analysis of the gaps in our knowledge concerning breast cancer risk

prediction and prevention. The clinical gaps included how to improve risk estimation, new chemopreventative

agents and optimal measures for lifestyle intervention. The laboratory gaps included the mechanism of the

effectsofpregnancy,energyrestrictionanddensityonthebreastandwhy,insomewomen,thereisalackof

involution of the breast after the menopause.

The discovery of the BRCA1 and BRCA2 genes revolutionised the management of women at high risk of breast

cancer. We reported that the uptake of gene testing was doubled after the publicity surrounding Angelina

Jolie’s BRCA positive gene test and subsequent bilateral risk reducing mastectomy. We, and others, have

demonstratedtheeffectivenessofriskreducingsurgeryforpreventingbreastcancerinwomenatveryhigh

riskandalsothatscreeningwithMRIisalsohighlyeffectiveinthisgroupofwomen.Preciseindicatorsofriskof

breastcancerinBRCA1/2carriersareimportantformanagement.Wereportedupdatedfiguresonpenetrance

thatindicatethatitisincreasingovertheyears.Penetrancemaybemodifiedbytheeffectsofsinglenucleotide

polymorphisms found in whole genome breast cancer association studies. However, attempts at selection of

candidatemodifiergenesandtelomerelengthdonotmodifyBRCA1/2andBRCA2penetrance.

The risks of women referred to the Family History Clinic but who are non-gene carriers can be accurately

predicted by using degree of family history and modifying this prediction by adding hormonal risk factors such as

ageoffirstpregnancy.However,mostwomeninthegeneralpopulationarenotawareoftheirrisks.Wetherefore

evaluated whether risk could be assessed in women at screening by mammography (PROCAS: PRediction Of

Cancer At Screening). Over 54,000 women entered the study which demonstrated that approximately 10%

of women are at moderate or high risk of breast cancer. We have preliminary evidence that more precise risk

estimation is possible if the mammographic density and SNPs are added to a standard model. Further work

is required to determine whether such models can be used in the National Breast Screening Programme to

determine the optimal interval for screening and the use of preventative measures.

Studies reported this year indicate progress in the endocrine prevention of breast cancer. Aromatase inhibitors

(AIs) lower oestrogen concentrations and have been shown to be superior to tamoxifen for the prevention of

systemic relapse after surgery for breast cancer. Now, in a study reported by our group earlier this year (the

IBIS-II),theAIanastrozole,whengivenforfiveyears,preventsbreastcancertoagreaterextentthantamoxifen

witharelativelylowsideeffectprofile.HoweveranimportantsideeffectofAIsisreductionofbonedensitybut

now we have shown that this can be abrogated by the bone sparing bisphosphonate once-weekly. Tamoxifen,

alsogivenforfiveyears,isnowacceptedbyNICEforbreastcancerprevention.Withlongerfollowupwehave

shownthatthepreventativeeffectcontinuesforupto20years(theIBIS-Itrial)buttheuptakeoftamoxifenin

women at risk of breast cancer remains relatively low.



Caroline Dive, Fiona Blackhall, Phil Crosbie, Rajesh Shah

Circulating tumour cell (CTC) research in early stage, resectable non-small cell lung cancer (NSCLC)

A collaboration of the early stage lung cancer and biomarker theme researchers

of the MCRC Lung Group aims to improve knowledge of metastasis.

Lung cancer is the most common cause of cancer-related mortality worldwide

(~1.4 million deaths/year). Five-year survival in the UK is less than 10%. The

most common pathological subtype, non-small cell lung cancer (NSCLC),

accounts for 85% of cases. Early diagnosis and surgical resection of NSCLC can

produce long-term survival (5-year survival: Stage I 58-73%, Stage II 36-46%,

Stage IIIA 24%). However, tumour recurrence occurs in 50% of cases indicating

micro-metastatic disease present at surgical resection undetected by current

stagingstrategies.Recurrenceriskpeaksduringthefirsttwoyearsaftersurgery

most commonly occurring at distant sites when it is almost universally fatal.

Platinum-based adjuvant chemotherapy improves survival by approximately 5%

inpatientswithstageII-IIIA,butbenefitinstageI,where5-yearmortalityis27-

42%, is unproven. To improve outcomes from lung cancer we need to increase

our understanding of the molecular mechanisms of metastasis in early stage

disease to exploit for therapeutic control: this may reveal new drug targets to

pursue in trialsof novel adjuvant therapies.Themore accurate identification

of patients most at risk of recurrence would also enable current management

protocols to be optimised.

In 2014, Dr Phil Crosbie, Senior Clinical Lecturer at The University of Manchester

and Honorary Consultant Respiratory Physician at University Hospital of South

Manchester NHS Foundation Trust (UHSM), in partnership with Professor

Caroline Dive and Dr Fiona Blackhall, secured funding from The Roy Castle

Lung Cancer Foundation (RCLCF) (~£26k) and the Moulton Charitable

Foundation (~£226K) for the conduct of two innovative clinical trials focused

on the detection and study of the molecular biology of circulating tumour cells

(CTCs) in early stage NSCLC. This work closely maps key research objectives of

CancerResearchUK’sfirstLungCancerCentreofExcellenceand isbased in

Professor Caroline Dive’s Clinical and Experimental Pharmacology group (CEP)

at the CRUK Manchester Institute (MI). Here we describe the rationale behind

both studies and how increasing our knowledge of CTCs will further shape our

understanding of this deadly disease.


An investigation of a novel CTC detection device in NSCLC.

CTCs are rare cells that can be detected in blood which are thought to form a

critical step in the development of metastatic disease. Evidence for the tumour

initiating potential of CTCs has been recently shown in xenograft models of

breast and, in Manchester, in small cell lung cancer. The potential for CTCs to be

used as prognostic and predictive biomarkers in advanced lung cancer has been

demonstrated in a number of studies but their application in early stage disease

has been limited by low sensitivity of detection. Addressing the challenge of low

detection is a critical area of CTC research and fundamental to the study of

CTCbiology.Theprimaryaimofthisfirststudyistodeterminewhethermore

CTCs can be detected in the peripheral blood of patients with lung cancer

using a novel CTC detection platform (CellCollector™, GILUPI) compared to

the current ‘gold standard’ (CellSearch®; Janssen Diagnostics). CellSearch®

automatically enriches CTCs by immunomagnetic selection of epithelial cell

adhesion molecule (EpCAM) expressing cells in blood (7.5ml), followed by

semi-automated morphological and immunofluorescent categorisation and

enumeration. CTCs detected in this way have been associated with a worse

prognosis in several solid tumour types including lung cancer. We previously

demonstratedthatinadvancedNSCLC,patientswith≥5CTCs/7.5mlbloodhad

a significantly poorer progression free andoverall survival, however ≥2CTCs

were seen in only 32% stage IV and rarely in stage III disease. Dr Crosbie led a

pilotinearlystageNSCLCthatdemonstrated≥2CTCs/7.5mlperipheralblood




inonly2/34(6%)patients.Weconcludedthatthismayreflectlackofassaysensitivityduetodown-regulation

of EpCAM and cytokeratins during epithelial to mesenchymal transition (EMT) as well as lower prevalence of

CTCs in early disease.

CellCollector™ is a novel CE approved medical device developed by German company GILUPI GmbH. The

device is a functionalised guidewire labelled with antibodies to EpCAM, which is designed to isolate EpCAM+

CTCs from peripheral blood through specific antigen-antibody binding. However, rather than analysing a

small volume of blood, the wire is placed through a standard intravenous cannula into a peripheral vein for a

periodof30minutes;thisresultsinasignificantlyincreasedsampledbloodvolume,estimatedtobe1.5to2

litres,or≈200timesthebloodvolumesampledbyCellSearch®(7.5ml)potentiallyincreasingCTCdetection

significantly.WewillexaminethisdeviceinpatientswithearlystageNSCLCandwillalsoexplorethefeasibility

of downstream molecular characterisation of CTCs.

Does the tumourigenicity of CTCs in early stage NSCLC predict disease recurrence?

It has been assumed for most tumour types that CTCs are the mediators of metastatic spread, but until

recently this assumption had not been formally tested. Using blood from patients with small cell lung cancer

(SCLC), where CellSearch® detected CTCs are relatively abundant, MCRC researchers from Professor Dive’s

CEP group, the University and The Christie demonstrated that CTCs enriched from SCLC patients routinely

form tumours in immune-compromised mice (Figure1A), termed CTC explant models or CDX. Histological

analysis demonstrated CDX were SCLC (Figure 1B) and genetic comparison of the CDX and single CTCs

isolatedfromthesamepatientconfirmedCDXsarederivedfrompatientCTCs(Figure1C).

Figure 1A. CDX derived from SCLC CTCs enriched from blood samples from two patients (patients 2 and 4).

Figure 1B. Comparison of IHC staining of patient 2 pleural fluidor patient 4 diagnostic biopsy and corresponding CDX.

Figure 1C. Whole genome sequencing of CDX2 revealed a c.440T>G transversion in TP53. Sanger sequencing on 6 single CTCs isolated from patient 2 demonstrated the same transversion, which was absent in the leukocyte sample, confirming acancer cell somatic mutation.

Figure 1A.

Figure 1C.

Figure 1B.



More recently in a proof of concept experiment, a CDX was successfully generated from blood taken from

apatientwithadvancedNSCLC.Pathologicaland immunologicalprofilingof theCDXmatchedtheprimary

tumour (Figure 2). Dr Crosbie’s focus will be to determine whether CTCs enriched from patients with early

stage NSCLC form CDX and to correlate CDX generation with clinical outcome.

This study will recruit patients undergoing surgical

resection of early stage NSCLC at UHSM where in excess

of 400 resections a year are performed. Dr Crosbie has, in

collaboration with Mr Rajesh Shah, lead Thoracic Surgeon

at UHSM, explored pulmonary vein sampling as a method

for increasing CTC detection in early stage NSCLC. The

pulmonary veins drain blood directly from the lungs; proximity

to primary tumour and blood draw prior to capillary bed

filtering,reportedtoremove90%ofCTCs,makespulmonary

vein sampling at surgery potentially advantageous. Previous

studies (using a variety of CTC enrichment methods) have

reported pulmonary vein CTCs in 18-96% of patients with

the presence of CTCs variably associated with prognosis.

At UHSM blood is taken prior to tumour manipulation

or vessel ligation to minimise artificial elevation in CTC

number. Pilot data has demonstrated pulmonary vein CTCs

(CellSearch®) inmorepatients(≥2CTCs:pulmonary14/34,

Figure 2. H&E staining of biopsy from the NSCLC patientwhose CTCs gave rise to CDX and of the derived CDX (top images). TTF1 and cytokeratin staining of the NSCLC CDX tumour (bottom images).



41% vs. peripheral vein 2/32, 6%; p=0.001) and in higher numbers (pulmonary 0-3093 vs. peripheral vein 0-4

CTC/7.5ml; p=0.002) than matched peripheral blood (Figure 3).

Pulmonaryveinbloodwillbetakenatsurgery,depletedofredandwhitebloodcellsandimplantedintotheflank

of an immune-compromised mouse. A matched tumour biopsy will be implanted into a second mouse. The

implantation of tumour biopsies to establish patient derived xenografts (PDX) is a well-described technique

that preserves tumour architecture and maintains tumour-stromal interactions allowing assessment of

tumour biology and treatment responses. In NSCLC, the successful establishment of PDX models has been

reported in 25-46% of cases; although PDX generation was linked to disease recurrence post-resection in one

study, the other studies show no correlation with clinico-pathological factors. Once established, response to

chemotherapy in PDX models may predict response in a clinical setting. However, PDX, established using small

singlesitetumourbiopsiesmaynotreflectthefullextentofintra-tumourheterogeneity,postulatedtobean

important driver of disease progression, treatment resistance and a risk factor for disease recurrence after

surgery. It therefore follows that PDX may not be representative of the cells responsible for distant metastatic

spread and disease recurrence in resected early stage patients. On the other hand, the tumourigenicity

(definedbyCDXgeneration)inmiceofcellsthathavealreadyinvadedthroughtissueandintravasatedasCTCs

in the patient may be a much better predictor of a patient’s recurrence risk, the hypothesis that will be tested

in this study.

Figure 3. Pulmonary vein sampling at the University Hospital of South Manchester and an image of a CellSearch detected CTC and WBC. CellSearch CTC enrichment is performed automatically by immunomagnetic selection of EpCAM (epithelial cell adhesion molecule) expressing cells, followed by semi-automated morphological and immune-fluorescent categorisation. Definition of a CTC: EpCAM and cytokeratin (CK; 8, 18 and 19) co-expression,4',6-diamidino-2-phenylindole (DAPI) positive nuclear staining and negative white blood cell marker (CD45) expression.



As a result of this study, we hope to be able to stratify early stage NSCLC patients according to risk of recurrence

whomaybenefitfromadjuvantchemotherapy,administeredatpointofconfirmedtakeoftheirderivedCDX

and/or PDX. These patients would also be subjected to more intensive follow up. Our ultimate goal is to identify

amarkerwithinblood to tailor adjuvant treatment topatientswho shouldderivemostbenefit.To achieve

this, the molecular landscape of CDX/PDX will be investigated using next generation sequencing platforms.

For patients whose CTCs and/or resected tumour fragment generated CDX/PDX respectively, a comparison

at the genomic level will also be made with CTCs isolated at resection, resected primary tumour and, when

available, recurrent tumour biopsy. By determining the response of CDX/PDX to chemotherapy regimens, we

hopetoselectaspecificandpersonalisedtherapyregimenforpatientsatpointofdiseaserecurrence.The

datagenerated fromthisstudywillalsocontributetotheongoingdrugtargetdiscoveryefforts forNSCLC

led by Dr John Brognard and Dr Michela Garofalo and work in drug discovery led by Dr Donald Olgivie at the

CRUK MI.



Claudia Wellbrock

Heterogeneity in Melanoma

The genetic and phenotypic heterogeneity found within melanomas is an

important feature to consider in the development of melanoma therapies,

because the communication between melanoma cell subpopulations can

impact on the efficacy of cancer drugs. Dr ClaudiaWellbrock’s laboratory is

investigating how intra-tumour signalling amongst different cell populations

controls melanoma growth and therapy response.

Our work has revealed that within a heterogeneous tumour there are distinct

subpopulations of melanoma cells that respond differently to the currently

applied MAP-kinase pathway targeting therapies. These subpopulations can be

distinguishedaccordingtotheirMITFexpressionstate.MITF,alineagespecific

transcription factor, is a crucial phenotype determinant and its expression is

distinctively heterogeneous throughout tumours. We have shown that MITF

confers resistance to MAP-kinase pathway therapy in melanoma. We found that

MITF is up-regulated in patients’ melanomas during treatment with MAP-kinase

pathway inhibitors. We discovered that this up-regulation is based on both cell

autonomous processes and signalling from the immune microenvironment.

Figure A heterogeneous tumour consisting of cells with a differentMITF expression state (high:red; low:green).


We have discovered that immune cells, in particular macrophages, can help

melanoma cells to survive and bypass MAP-kinase pathway targeted drug

action by producing the soluble factor TNFα. Moreover, when patients are

receiving treatment with the novel targeted drugs, macrophages produce

more TNFα, which confers resistance and makes treatment less effective.

Combining standard treatment with drugs that block TNFα action at the same

timecouldpotentially providemore long-lasting andeffective treatments to

increase survival.

One of the reasons why melanoma is such an aggressive cancer is its early

tendency to invade surrounding tissue. It is therefore important to understand

whatcontrolsmelanomainvasion.Usingazebrafishxenograftmodelallowed

us to make the striking discovery that in a heterogeneous setting, inherently

invasive cells co-invade with subpopulations of poorly invasive cells, a

phenomenon termed ‘co-operative invasion’. During co-operative invasion, the

invasive cells provide protease activity and deposit extracellular matrix (ECM).

Moreover, thepoorly invasivecellsnotonly ‘benefit’ fromtheheterogeneous

situation, but also alter the mode that the invasive cells use for invasion.

Ourdataidentifiedasofarneglectedpropertyofmelanoma,whichistheability

of melanoma cell subpopulations to cooperate within a heterogeneous tumour,

and this drives melanoma progression while at the same time preserving the

heterogeneity seen throughout tumour progression. We are currently assessing

the consequences of co-operativity in a broader sense and are investigating

how co-operative behaviour impacts on the response of melanoma cells to

MAP-kinase pathway targeted therapy.

Heterogeneity in Melanoma



Translating Cancer Biology into Novel Therapeutics in the Manchester Cancer Research Centre

The Drug Discovery Unit at the Manchester Cancer Research Centre (MCRC)

was established in 2009 to translate the fundamental biological research

conducted within the MCRC into novel therapeutic opportunities. Recent

advances have seen two key projects make substantial progress toward

clinical evaluation.

In late 2009, scientists at the Cancer Research UK Manchester Institute began

to unravel the biological role of a little-studied enzyme known as poly-(ADP-

ribosyl) glycohydrolase, or PARG. This enzyme functions in concert with the

PARP family of enzymes to alert cells to DNA single strand breaks, before

these lesions lead to genetic instability and damage. In recent years, the poly

(ADP ribose) polymerase (PARP) family of enzymes have been the subject of a

number of clinical trials, evaluating agents such as Olaparib from AstraZeneca

and Rucaparib from Clovis Oncology. Indeed, imminent European approval

of such agents highlights their clear therapeutic benefit in patients with

ovarian cancer.

DNA single strand breaks (SSBs) are the most common type of damage that

arises in cells. Upon damage, PARP binds to the SSB and auto-ribosylates itself

using NAD+ as a substrate. This generates chains of poly ADP ribose (PAR),

which provide a recruitment signal for repair complexes to accumulate at the

damage site and repair the lesion. Removal of the PAR chains, an essential step

to facilitiate access of this repair machinery, is accomplished by PARG, the only

enzyme known to efficiently catalyse the hydrolysis ofO-glycosidic linkages

of ADP-ribose polymers and thereby reversing the effects of PARPs. Total

PARGdeficiencyleadstocelldeathwhilstPARGdepletion,usingRNAi,leadsto

pleiotropiceffectssuchasPARchainpersistence,progressionofsingle-strand

to double-strand DNA lesions and NAD+ depletion (Figure 1). Ultimately, these

effectsshouldleadtocelldeathintumours,whereconsiderableDNAdamage

exists and alternate DNA repair pathways may be compromised.

As a therapeutic target, PARG has been largely unexplored to date. Suggestions

that the enzyme is ‘undruggable’ and scant literature information dissecting

its biological function have held back this area of research. However, work

Allan Jordan, Ian Waddell and Donald Ogilvie


within the Instituteand furtherafieldhassuggested thatPARGmayofferan

alternate therapeutic strategy to the more widely-investigated PARP inhibitors

in certain tumour types with increased genetic instability and compromised

DNA repair pathways.

TheDDUhasbeenactivelyinvestigatingthisnoveltargetsince2010butefforts

were initially hampered by difficulties in finding novel chemical compounds

which could form the basis of a drug discovery programme. In 2011 discussions

with AstraZeneca revealed that the company also had an interest in the target

and had potential startpoints which may be available to the DDU. Having

conducted a high throughput screen of 1.7M compounds, the AstraZeneca

teamhadidentifiedjustasingle‘hit’compound,highlightinghowcomplexthis

target was to prosecute. Crucially, the high-resolution crystal structure of this

compoundboundtohumanPARGhasbeenobtained,detailingspecificallyhow

the compound and PARG interacted on the atomic level. This information was

transferred to the DDU and work on the project began in earnest.

The team soon revealed that this early molecule could inhibit the action of

PARGinacellularcontextandwebelievethatthiswasthefirsttimethatrobust

cellular anti-PARG activity had been demonstrated. However, the compound

was also cytotoxic and suffered from poor physicochemical properties

that would preclude further development. Through expert computational

and medicinal chemistry design, strategies were enacted to ‘scaffold-hop’

away from this early hit into novel chemical matter and this approach yielded

several new chemical series for the group to investigate in a series of detailed

biological protocols.

Over the past two years, these chemical series have been refined and

optimised to deliver over a thousand-fold improvement in cellular potency

compared to the original hit and have delivered a much more drug-

like overall profile. These derivatives ablate the clonogenic potential of

certain tumour cell lines and we believe that we now understand at least

some of the factors which sensitise particular cell lines to PARG inhibition.

This information will be of critical importance in determining which




patients may respond best to these agents and will influence the design of clinical trials once we have

identified suitable candidatemolecules. Moreover, these compounds are well tolerated in vivo and show

promising pharmacokinetics which now allow the therapeutic role of PARG inhibition to be more

comprehensively investigated.

Critical in vivo studies are now underway within the Unit. Having demonstrated that our compounds can

engage with, and inhibit, PARG in tumours in vivo, leading to persistence of PAR chains, we are now determining

how this translates to inhibition of tumour growth in vivo.Theseexperimentswillhelpdefineourpathtoward

the clinical evaluation of these exciting and unique inhibitors.

WhilstPARGoffersanopportunitytounderstandandexploitnovelbiology,oureffortsontheREToncogenic

kinase recognises a therapeutic need for improved agents against a drug target which is already clinically

validated. The RET (Re-arranged during transfection) receptor tyrosine kinase is a known oncogene

which is implicated in certain subsets of medullary thyroid cancer (MTC) and 1-2% of non-small cell lung

cancers (NSCLC).

Whilst agents such as Vandetanib and Cabozantanib have recently been approved for use as RET inhibitors

inMTC,theiruseisnotwithoutcomplication.NeitheragentwasdesignedasaspecificRETinhibitorandthis

serendipitoussecondarypharmacologyistemperedbyconsiderableside-effectscausedbyinhibitionofother

kinases. These additional pharmacologies are dose-limiting, reducing the therapeutic utility of the agents in

the chronic clinical setting and have led to FDA ‘black box’ usage warnings for both compounds. We believe that

amoreselectiveRETinhibitorwouldbeofconsiderablebenefittopatients,allowingstrongertargetinhibition

and,therefore,increasedclinicalutilitywithreducedsideeffects.



Theteamhasspentconsiderabletimeandeffortdevelopingadetailedbiologicaltestingcascadethatallows

ustohighlightanysuperiorefficacyofourexperimentalagentsoverthosealreadyemployedclinically.Given

that the field of kinase inhibitors is heavily exploited in drug discovery, we have also developed innovative

approaches to reveal novel startpoints which we have now shown to be potent and selective inhibitors of RET at

both the enzyme and cell level. These diverse chemical derivatives show a range of physicochemical properties

and we are investigating their pharmacokinetics in more detail in order to prioritise those most likely to be

appropriate for further development. Our primary objective at the present time is to deliver molecules with

improvedpharmacokinetics,whilstmaintainingtheexcellentpotencyandselectivityprofileswehaveobtained.

These tool compounds will then facilitate early proof of concept experiments to demonstrate unequivocally

thatspecificandselectiveinhibitionoftheREToncogenewilldelivertherapeuticbenefitinRET-driventumour

xenograft models.

Resistance to targeted kinase inhibition is often observed through mutation of the enzyme, leading to

insensitivity of the tumour to the drug. This anticipated mechanism of resistance often arises through

alteration of a key area of the protein known as the ‘gatekeeper region’ of the kinase. Through computational

andbioinformaticsanalysis,webelievethatwehaveidentifiedthelikelyclinicalresistancemechanismand,to

circumvent the clinical implications of this issue, we have already begun the hunt for inhibitors of the resistant

enzyme. Having a second-line therapeutic approach in place in readiness for emergent resistant disease

should prolong the time over which we can control RET-driven disease in patients with NSCLC and, in doing so,

prolong overall survival.

To accelerate these studies, in November 2014 the Cancer Research Technology Pioneer Fund and Sixth

Element Capital announced that it had agreed to fund this project through to Phase I clinical trials. The fund,

a joint venture between Cancer Research Technology and the European Investment Fund, was established in

2012tohelpfillthefundinggapbetweenearlystageresearchandearlyclinicalevaluation.Thisfundingisthe

fourth investment made by the fund and provides us with access to increased capabilities and resources for

the project, in order to deliver a candidate molecule for pre-clinical evaluation before the end of 2016.



Further delivery of novel therapeutics will depend heavily on identifying emerging new therapeutic targets from

across the MCRC and a key activity in the team is to provide chemical tool compounds to help understand

emerging biology. Through the application of medicinal chemistry, we work closely with group leaders from

across the University to help identify, source and synthesise molecules which are not commercially available

but which may help to better understand certain biological processes. Through such interactions, we have

recently helped Cathy Tournier’s group uncover more details about the role of the ERK5 kinase in epithelial

inflammation and the role thismay play in tumourigenesis, and provided Janni Peterson’s teamwith tools

to dissect the regulation of the mitotic regulator Wee1 by TOR signalling. Ultimately, these advances in the

understandingoftumourigenesisandcellcyclecontrolmayleadtotheidentificationofnewdrugtargetswhich

can be progressed by the team. More dramatically, our collaborative work with Tim Somervaille’s group on

LSD1 has not only helped his team deliver a more comprehensive understanding of the role of this exciting

epigenetic target in acute myeloid leukaemia (AML) but has highlighted the MCRC as a key centre for the

investigation of this disease. We were delighted that this expertise was recently recognised by the decision by

Oryzon Genomics to bring their Phase I clinical trial of irreversible LSD1 inhibitors to The Christie, with Tim as

leadinvestigatoronthetrial.WefeelthisembodiesthebenefitsofcollaborativeresearchacrosstheMCRC,

deliveringearlyaccesstoemerging,first-in-classtreatmentstopatientsintheNorthWestandwehopethisis

thefirstofmanysuchtrialsweareabletohelp,insomeway,todeliverintoTheChristie.

Moving forwards, we expect that this will not be our only involvement in bringing new clinical trials to Manchester.

Over the coming months we will be further enhancing our internal target validation capabilities, increasing

oureffortsalongsideMCRCgroup leaders tostrengthentheclinical linkage foremerging targetsandbuild

confidenceintheirpotentialtractabilityasnoveldrugdiscoveryprogrammes.Thiswillallowustomaintainan

activeanddynamicportfolio,ensuringaflowofqualitytargetsintotheteam.AsourinvestmentsinPARGand

RETmovetheseprojectstowardclinicaldevelopment,thisinfluxofnewertargetswillbeimportanttomaintain

our delivery ambitions.

With the increased funding for RET now available to us, we anticipate that the next 18 months will be critical for

the project and our ambition is to accelerate the pace of our research to deliver novel candidate molecules for

pre-clinical evaluation at the end of this timeframe. Along similar lines, we anticipate that over the next year we

will secure a development partner for PARG. This partnership will draw in additional resources and greatly assist

inoureffortstonarrowdownourinitialpatientpopulationforclinicalevaluation.Thesewiderexperimentswill

thenbeusedtodefineourpaththroughpre-clinicalevaluationand,ultimately,ourearlyclinicaltrialformat.

The past two years have seen considerable progression of our internal and collaborative research portfolio;

our ambition over the next two years is to translate these dramatic advances into small molecules with the

potential for evaluation in a Phase I patient cohort.



Collaboration pays dividends for leukaemia research

Touched upon in the report from the Drug Discovery Unit was their collaboration

with Leukaemia Biology on LSD1 inhibitors – this success embodies the bench-

to-bedside approach of the MCRC.

In 2010 William Harris, a graduate student in the Leukaemia Biology group,

performed a small-scale screen of candidate epigenetic regulators in leukaemia.

ThesehadbeenidentifiedinamicroarrayexperimentwehadpublishedinCell Stem Cell in 2009 as expressed highly in murine Mixed Lineage Leukaemia

stemcells(MLLLSC)anddownregulatedwiththeirdifferentiationandlossof

stem cell potential. Bill noticed that knockdown of one of these genes, LSD1,

led toLSCdifferentiation. LSD1 is a histonedemethylasewhich is known to

remove methylation marks from histone tails, potentially thereby regulating

gene expression. He searched the literature for compounds known to inhibit

LSD1 and identified themonoamine oxidase inhibitor tranylcypromine. This

drug has been in routine clinical practice for several decades in the treatment of

depression and irreversibly inactivates LSD1 with an IC50of5-20μM.Remarkably,

whenappliedtoMLLLSCitpromotedcelldifferentiationinasimilarmannerto

LSD1 knockdown.

To identify compound classes that might serve a useful role in the clinic, we then

initiated a collaboration with the Cancer Research UK Manchester Institute’s

DrugDiscoveryUnit.AllanJordanandJamesHitchinidentifiedarecentlyfiled

patent reporting substantially more potent and selective inhibitors of LSD1.

These inhibitors are chemicallymodified versions of tranylcypromine, and it

is thechemicalmodificationof tranylcyprominewhichconfers theenhanced

potency and selectivity. James Hitchin synthesised one of these compounds

for us and we were able to demonstrate that, in the nanomolar range, we were

abletopromoteLSCdifferentiationin in vitro and in vivo assays using murine

and human cell lines and also patient cells.

Our work, which was published in Cancer Cell in 2012, has led to a fruitful

collaboration with Oryzon Genomics, based in Barcelona, Spain. It was this

companythathadfiledthepatentforthenewermorepotentLSD1inhibitorswe

were able to synthesise for our experiments. Our work enabled Oryzon to push

Tim Somervaille


ahead with a clinical trial focus for their advanced lead compound ORY1001,

giventheselectivesignalforLSD1inhibitorefficacyinleukaemiaversusother

sub-types of malignancy. It further enabled Oryzon to acquire orphan drug

status for ORY1001 for the treatment of acute myeloid leukaemia from the

European Medicines Agency in 2013, a designation designed to facilitate the

development of new medications for rare diseases.

The phase I trial of ORY1001 opened in July 2014 at the Hospital Universitari Vall

d’Hebron in Barcelona and The Christie NHS Foundation Trust in Manchester,

withTimSomervailleastheUKChiefInvestigator.Thisisafirst-in-class,first-

into-man early phase trial of LSD1 inhibition in acute leukaemia, with a particular

focus on uncovering the pharmacokinetic and pharmacodynamic properties

of this completely new medication. Patients receive cycles of oral therapy as

in-patients, and later as out-patients, and their disease parameters are very

carefully monitored. Recruitment is proceeding well and preliminary results of

the trial should become available during the course of 2015.

Collaboration pays dividends for leukaemia research



Ovarian cancer and angiogenesis

MCRC researchers have a particular interest in understanding angiogenesis in

ovarian cancer.

Angiogenesis has emerged as a novel target for anti-cancer therapies

through randomised clinical trials that have tested the benefit of adding

vascular endothelial growth factor (VEGF) inhibitors, such as bevacizumab, to

conventional cytotoxic therapies. Despite improvements in progression-free

survival,thebenefitinoverallsurvivalhasbeenmodest.Tumourangiogenesis

is regulated by a number of angiogenic cytokines. Thus innate or acquired

resistance to VEGF inhibitors can be caused, at least in part, through expression

of other angiogenic cytokines, including fibroblast growth factor 2 (FGF2),

interleukin 8 (IL-8) and stromal-cell-derived factor 1α (SDF-1α), which make

tumours insensitive to VEGF signalling pathway inhibition.

The activity of most angiogenesis-related growth factors is regulated by

heparan sulphate (HS), which is essential for the formation of FGF2/FGF

receptor (FGFR) and VEGF(165)/VEGF receptor signaling complexes. HS is a

component of cell surface and extracellular matrix proteoglycans that regulates

numerous signaling pathways by binding and activating multiple growth factors

and chemokines. The structural characteristics of HS that determine activation

or inhibition of such signaling complexes are only partially defined, but the

amount and pattern of HS sulphation are key determinants for the assembly of

the trimolecular, HS-growth factor-receptor, signalling complex.

The Translational Angiogenesis group, led by Professor Gordon Jayson,

showed that ovarian tumour endothelium displays high levels of HS sequences

that harbour glucosamine 6-O-sulphates when compared with normal

ovarian vasculature. Reduced HS 6-O-sulphotransferase 1 (HS6ST-1) or

6-O-sulphotransferase 2 (HS6ST-2) expression in endothelial cells impacted

upon the prevalence of HS 6-O-sulphate moieties in HS sequences, which

consist of repeating short, highly sulphated S domains interspersed by

transitionalN-acetylated/N-sulphateddomains.Wesawthata≤40%reduction

in 6-O-sulphates significantly compromised FGF2- and VEGF(165)-induced

endothelial cell sprouting and tube formation in vitro and FGF2-dependent

Gordon Jayson


angiogenesis in vivo. Moreover, HS on wild-type neighbouring endothelial

or smooth muscle cells failed to restore endothelial cell sprouting and tube

formation. The affinity of FGF2 for HS with reduced 6-O-sulphation was

preserved, although FGFR1 activation was inhibited, correlating with reduced

receptor internalisation. We concluded that 6-O-sulphate moieties in

endothelial HS are of major importance in regulating FGF2- and VEGF(165)-

dependent endothelial cell functions in vitro and in vivo and highlighted HS6ST-1

and HS6ST-2 as potential targets of novel antiangiogenic agents.

We then demonstrated that HS6ST-1 and HS6ST-2 play a direct role in

ovarian cancer angiogenesis. Down-regulation of HS6ST-1 or HS6ST-2 in

human ovarian cancer cell lines resulted in 30-50% reduction in glucosamine

6-O-sulphate levels in HS, thus impairing HB-EGF-dependent EGFR signaling

and diminishing FGF2, IL-6, and IL-8 mRNA and protein levels in cancer cells.

These cancer cell-related changes again reduced endothelial cell signaling

and tubule formation in vitro. In vivo, the development of subcutaneous

tumournoduleswithreduced6-O-sulphationwassignificantlydelayedatthe

initial stages of tumour establishment with further reduction in angiogenesis

occurring throughout tumour growth. Our results showed that in addition

to the critical role that 6-O-sulphate moieties play in angiogenic cytokine

activation, HS 6-O-sulphation level, determined by the expression of HS6ST

isoforms in ovarian cancer cells, is a major regulator of angiogenic program in

ovarian cancer cells impacting HB-EGF signaling and subsequent expression of

angiogenic cytokines by cancer cells.




Targeting multiple angiogenic cytokines with HS mimetics may represent an opportunity to inhibit tumour

angiogenesismoreefficiently.Ourpublishedstudiesandunpublishedworkhavedemonstratedthefeasibility

of generating synthetic HS fragments of defined structure with biological activity against a number of

angiogenic cytokines.

Working in conjunction with the Clinical and Experimental Pharmacology group, the Translational Angiogenesis

group has also been exploring potential predictive biomarkers for existing anti-angiogenic therapies. The

modest improvement in survival seen in trials of such agents has sparked interest in developing measures that

couldallowclinicianstoselectwhichpatientsaremostlikelytobenefit,whileminimisingtoxicity.Weanalysed

patient blood samples from the international ICON7 trial, which investigated the addition of bevacizumab to

conventional cytotoxic therapy in ovarian cancer.

Using multiplex ELISAs previously developed and validated to Good Clinical Practice standards, we determined

the pre-treatment plasma concentrations of 15 angiogenesis–related factors implicated in VEGF biology

(VEGFA,-C,and-D;andVEGFreceptors,VEGFR1,andVEGFR2),angiogenicfactorsinovariancancer(fibroblast

growth factor, FGF2; interleukin, IL8; angiopoietin, Ang1 and Ang2; and Tunica internal endothelial cell kinase

2, Tie2), or potential mediators of resistance to VEGF (placental growth factor, PlGF; FGF2; platelet-derived

growth factor, PDGFbb; granulocyte colony–stimulating factor, GCSF; or hepatocyte growth factor, HGF) and

investigated their predictive significance.We fitted aCoxmodel of PFS for each distinct combinationof a

putativebiomarkerandtreatmentandusedaKaplan-MeierestimatortovisualisethePFSforeachidentified

putative biomarker.

Two striking observations emerged: (i) for Ang1, as a linear model on the nontransformed continuous scale,

therewasaclearsuggestionofaninteraction,and(ii)forTie2,althoughtherewasnosignificantinteraction

term, there was clear evidence of heterogeneity in the relation between high levels of Tie 2 and treatment. For

women with high Ang1/low Tie2 values, treatment with bevacizumab had an expected HR of 0.21 for PFS when

comparedwithstandardtreatment.ThebiologicimplicationofthesefindingisthattheAng1–Tie2axismay

play a pivotal role in mediating resistance to VEGF pathway inhibitors.

The teamhas identified that the angiopoietin signalling systemprovides predictive information that could

optimise the use of VEGF pathway inhibitors in the treatment of ovarian cancer. Further as yet unpublished

data have shown that the angiopoietin family of molecules also provides information on the development of

resistancetoVEGFinhibitors.Whileconfirmatorystudiesareplanned,iftheresultsarevalidatedtheworkwill

allow the investigators to identify whom to treat with VEGF inhibitors and alert the treating team to the onset

of vascular resistance to these drugs so that new agents can be instituted.

Inthe laboratory,theteamhasdeterminedthestructuresofsyntheticoligosaccharidesthat inhibitdefined

angiogeniccytokines;providing thefirstevidence forstructural specificity in thisfieldand therebyopening

the door to a new family of saccharide-based anti-angiogenic therapeutics that would address the resistance

identifiedthroughthebiomarkerprogrammedescribedabove.



Key role for Radiotherapy in personalised approach to cancer treatment

Highprofilerecruitmentandconfirmedfundingfornewcutting-edgefacilities

combine with a strong research output to result in a successful two years for

Radiotherapy-Related Research at the Manchester Cancer Research Centre.

International expertise in physics has been strengthened by two Chair-level

appointments. Professor Marcel van Herk, a world-renown radiotherapy

physicist currently based at the Netherlands Cancer Institute in Amsterdam, will

move to Manchester in April 2015. Professor van Herk has carried out pioneering

workinthefieldofimaginginradiotherapyandearlyinhiscareerdevelopedan

electronic portal imaging system that has since been commercialised and used

worldwide. More recent work has continued to pioneer innovative approaches

to the application of image-guided intensity-modulated radiotherapy.

A second appointment will drive forward research in proton therapy. Manchester

has recruited Professor Karen Kirkby, who has a particular interest in ion beam

therapyanditsbiologicaleffects,asChairinProtonTherapyPhysics.Professor

Kirkby was previously Director of Science for the Surrey Ion Beam Centre and

played a key role in getting proton therapy on the political agenda.

The last two years have also seen progress towards the establishment of both

proton therapy and novel image-guided radiotherapy facilities in Manchester.

FollowingconfirmationoffundingfromtheDepartmentofHealthforaProton

Therapy Centre to be located at The Christie, research groups have received

approval to include an additional gantry in order to establish a proton research

facility. Within the University’s School of Physics, Dr Hywel Owen is leading

research into accelerator technology, the development of Monte Carlo codes

and methods for particle tracking, and the design of novel storage rings for

synchrotron radiation.

Plans to replace the research radiotherapy linac in the Wade Centre at The

Christie were boosted by the announcement that Manchester had joined

Elekta’s international collaboration to develop a magnetic resonance (MR)

image-guided radiotherapy system. A prototype MR Linac has been developed

in Utrecht and now we have the opportunity to contribute to the clinical

implementation of this cutting-edge technology.

Tim Illidge, Catharine West and Nick Slevin


The Translational Radiobiology group investigates potential prognostic and

predictive biomarkers, and in particular is interested in assessing radiosensitivity,

predicting late radiation toxicity effects and exploring the utility of hypoxia-

modifying agents. Two collaborative publications have made use of several

sets of radiogenomic study data: RAPPER (Radiogenomics: Assessment of

Polymorphisms for Predicting the Effects of Radiotherapy), RADIOGEN and

Gene-PARE(GeneticPredictorsofAdverseRadiotherapyEffects).Agenome-

wide association study in prostate cancer patients, in conjunction with groups in

Santiago de Compostela, Spain, University of Cambridge and Mount Sinai New

York,identifiedasusceptibilitylocusforlateradiotherapytoxicityat2q24.1.This

locus comprises TANC1, which is known to play a role in regenerating damaged

muscle. A larger study, exploring association of common SNPs with toxicity two

years after radiotherapy in 1850 breast and prostate cancer patients, provided

evidence of a relationship. 2014 also saw the start of the REQUITE project, which

aims to validate predictive models of radiotherapy toxicity alongside biomarkers

of radiosensitivity. The international study will collect patient-reported outcome

and quality of life data from 5,300 radiotherapy patients. Such a patient-centred

approach to assessing toxicity has been demonstrated by the Radiotherapy in

LungCancergrouptobeeffectiveinalungcancerpatientcohort.

Duetothekeyroleplayedbyoxygenationindefiningradiosensitivity,Professor

Catharine West’s group has also been developing gene-based hypoxia

signatures and investigating the potential of such signatures and other hypoxia

measures to predict benefit from hypoxia-modifying therapy. In a cohort of

high-riskbladdercancerpatients,necrosiswasshowntopredictbenefitfrom

hypoxia modification. Within the same cohort of patients from the BCON




(bladder carbogen nicotinamide) trial, we found that those with high HIF-1αexpressiongainedbenefitfromthe

additionofcarbogenandnicotinamidetostandardradiotherapy,whereasnobenefitwasseenwithlowHIF-1α.

A study looking at the BCON cohort alongside laryngeal cancer patients enrolled on the ARCON (accelerated

radiotherapy with carbogen and nicotinamide) trial demonstrated that a 26-gene hypoxia signature predicted

benefitfromthehypoxiamodifyingtherapyinlaryngealbutnotbladdercancer.

Within the Targeted Therapy and Experimental Oncology groups, there is a shared interest in using novel

immunomodulatory agents to potentiate the effect of ionising radiation. In 2014,we reported pre-clinical

experiments using a systemically administered Toll-like receptor 7 agonist and showed that administration

of this agent in combination with ionising radiation primes an antitumour CD8+ T-cell response leading

to improved survival in colorectal carcinoma and fibrosarcoma models. In addition, efficacy extended

outside the irradiationfield, reducingmetastatic load.Asecondstudyevaluatedanapproach toovercome

acquired resistance to fractionated radiotherapy. We demonstrated that radiotherapy leads to an adaptive

upregulation of PD-L1 expression in tumour cells that is dependent on CD8+ T-cell production of IFNγ and

mayattenuate theefficacyof the anticancer immune response.By deliveringmAb targeted againstPD-1

andPD-L1,wewereabletoenhancetheefficacyoflowdosesoffractionatedradiotherapy.Dosescheduling

for the anti PD-L1 agent was critical, with effective anti-tumour effects only seen with concurrent not

sequential administration.

Professor Tim Illidge’s group are also involved in trials of radioimmunotherapy agents. At the beginning of 2014,

resultswere reported froman internationalmulti-centrephase II trial evaluating theefficacy andpotential

toxicity of fractionated 90Y-ibritumomab tiuxetan (90Y-IT) as an initial therapy for follicular lymphoma. The study

demonstrated that fractionated radioimmunotherapy using this agent was effective and well-tolerated in

patients with advanced stage disease.

Investigators at The Christie have led several trials looking at methods to improve outcome in head and neck

cancer.NIMRAD is a phase III trial investigating the use of hypoxiamodification in the formof nimorazole

alongsideIMRT,withaparticularaimtoassessthebenefit inpatientswhoarenotsuitableforsynchronous

chemotherapyorcetuximab.Itishopedthatthisstudywillleadtomoreeffectivetreatmentoptionsforsuch

patients,whoaretypicallyelderlyorinfirm.



Imaging Science research at the MCRC

Advanced imaging methods play a core role in cancer research, particularly in

thefieldsofradiotherapyrelatedresearch,drugdevelopmentandpersonalised

medicine. Developing and translating validated imaging biomarkers is a

significantchallenge,butonethatiscentraltotheaimsoftheMCRC.

Imaging research within the MCRC has been bolstered substantially by nearly

£9M funding from Cancer Research UK (CRUK) and the Engineering and

Physical Sciences Research Council (EPSRC) to establish a joint cancer imaging

centre between The University of Manchester and the University of Cambridge.

Thisawardbegan inDecember2013andwill run forfiveyears.Thestrategic

importance of the funding was summed up by Dr Iain Foulkes, Cancer Research

UK’s executive director of strategy and research funding, who said: “Imaging is

aninvaluabletoolinthefightagainstcancer.Beingabletoseewhat’shappening

inside a patient is vitally important in understanding how treatments are working

and the best ways to improve them”.

As part of the CRUK-EPSRC Cancer Imaging Centre, scientists within the

MCRC undertake world-class research using a variety of techniques, such as

bioluminescence and optical microscopy, MRI (Magnetic Resonance Imaging)

and PET (Positron Emission Tomography). This latest funding has helped to

recruit PhD students, clinical fellows and post-doctoral researchers who are

helping a number of PIs to develop new imaging techniques and applications.

Our portfolio covers a range of projects centred on tumour angiogenesis,

hypoxia, cell signalling and death that link into the three research themes

identifiedpreviouslyintheMCRC,namely(1)thedevelopmentandvalidationof

imaging biomarkers; (2) development of preclinical imaging and (3) translational

imaging research. Particular focus is made on two cancer types – lung and brain

–thatareidentifiedbyCRUKascancersofunmetneed.

Imagingbiomarkervalidationandqualification

All biomarkersmust be validated and then qualified for clinical use. Imaging

biomarkers are no exception and the series of steps required to validate

an imaging biomarker differ from biospecimen biomarkers. CRUK and the

European Organisation for Research and Treatment of Cancer (EORTC) have

recognisedthesekeydifferencesandinvestigators inManchesterare leading

JamesO’Connor,AdamMcMahon,GeoffParker,KayeWilliamsand Alan Jackson



aninternationalconsensusefforttoproducearoadmapforimagingbiomarker

studies in oncology. This work has been led by CRUK Clinician Scientist Dr

James O’Connor, Professor John Waterton and Professor Alan Jackson and

has over 75 collaborators from major European and North American institutions

including the NIH/NCI.

The philosophy espoused in this initiative has potential to transform the way in

which imaging biomarker science is carried out internationally. The initial output

has already been adopted by CRUK as criteria for assessing imaging biomarker

applications and a landmark paper will be published in early 2016 in Nature Reviews Clinical Oncology. This has already helped to consolidate the MCRC’s

position as a world leader in both biospecimen and imaging biomarker science.

Tissue microstructure evaluation with MRI

Imaging tissue microstructure in vivo may provide a clinical tool for detecting

tumour cell proliferation and death and tumour infiltration into neighbouring

healthy tissues. Tissue microstructure can be assessed using diffusion

magneticresonanceimaging(dMRI)whichissensitivetothediffusionoftissue

water over distances of a few microns. However, clinical use of dMRI has two

significantlimitations:Firstly,itisimpossibletorelatechangesintheapparent

diffusioncoefficient(ADC)ofwatertochangesincellsize,packingdensityor

membranepermeabilityunambiguouslytocancercell infiltration,proliferation

and therapy response. Secondly, current strategies for reducing the corruption

of dMRI data due to motion are unsatisfactory and can blur tumour features or

substantially extend scan durations.



Work ledbyProfessorGeoffParkerhasdemonstrated thatdMRIcanquantify tissuemicrostructure in the

brain and other neural tissues, by measuring axon diameter in the whole brain. This principle has been extended

to measure tumour cell packing, density and cell membrane permeability. Further work has used an analytical

expression to create an interactive tool for exploring the signal changes arising for tissues with different

properties. This has shown that sensitivity to change in intracellular volume fraction is lower for larger cells than

smaller cells, and that the sensitivity varies with imaging sequence parameters. It has also allowed a comparison

of the signal changes predicted when cells shrink but density either changes or remains stable. This novel work

highlightsthecompetingeffectsofchangesincellsizeandvolumefractionondiffusionsignals(Figure1).

Figure 1: Interactive tool for evaluating tissue cell size and density Screenshotofthetoolshowssignalchanges(colours)asafunctionofpulsesequenceparameters(G,Δ,∂)andtissueproperties(R,Di,De,fi).Images courtesy of Dr Damien McHugh and Dr Fenglei Zhou.

These biomarkers are being validated using a number of strategies including novel tissue mimetic phantoms,

comparing MRI measurements with scanning electron microscopy and with micro-CT data performed at the

Henry Moseley X-ray Imaging Facility in Manchester. Once validated, the dMRI measurements will be tested in

clinical cohorts against other MRI biomarkers of the tissue microstructure including 23Na MRI, in collaboration

with Dr Ferdia Gallagher and colleagues in Cambridge.

ImagingoxidativedamageandinflammationwithnovelPETtracers

Positron emission tomography is an exquisitely sensitive imaging modality capable of yielding both images and

quantitative data regarding tracer uptake kinetics, distribution and excretion, using sub-microgram quantities

of tracer. Dr Adam McMahon is leading work to combine this sensitivity with the selectivity of antibodies

towardsspecificbiomolecules,whereantibodiesarechemically radiolabelledwithaPET isotope.Theteam

at the Wolfson Molecular Imaging Centre (WMIC) have already demonstrated ability to perform such labelling

experiments binding 89Zr to the two monoclonal antibodies: cetuximab and bevacizumab. 89Zr is used because



Figure 2: Mass spectroscopy imaging of tumour lipid metabolism A-H&EimageshowingtwoNSCLCtumours.B:MSimagesofthesametissue,showingthetumourspecificdistributionof a lipid species.

its half-life (3.27 days) allows the antibody to be imaged over the 2 – 3 day period required for the antibody to

reach its target. Future work will aim to improve this approach through the use of nanobodies (small fragments

of antibodies that retain the desired property of selective target recognition but due to their small size can

reach their targets within a few hours). Radiolabelling methods that chemically bond these nanobodies to the

PET isotope 18F have been developed, which give better quality PET images than 89Zr with less exposure to

radiation. Thefirstnanobodytobelabelledtargetsthemacrophagemannosereceptorallowingtheroleof

activatedmacrophagestobeimagedintumour-associatedinflammatoryprocesses.

To image oxidative damage, PET tracers are under development that will bind to radical sites in tissues

generated by exposure to ionising radiation (as in radiotherapy) or oxidative chemical insults (as experienced in

some types of chemotherapy).

Lipid Metabolism in Tumours

Tumourlipidmetabolismdiffersfromlipidmetabolismseeninhealthytissues.BothPETandmassspectrometry

(MS) imaging methods are being developed to image these differences, led by Dr Adam McMahon and

Professor Kaye Williams. PET powerfully allows metabolic processes to be imaged in real time but is sensitive

to only one substance (the PET tracer) at a time. To allow PET imaging of lipid metabolism we have radiolabelled

a fatty analogue ([18F]FTHA). MS imaging requires sections of surgically removed tissue but can potentially

image hundreds if not thousands of biomolecules or pharmaceuticals in that tissue section.

ThisisillustratedintheimagesinFigure2.EachMSimageshowsadifferentlipidcomponentofthetumours

anditisclearlyseenhowthetumoursandhealthysurroundingtissuesdifferintherelativeconcentrations

of the three lipids imaged. The non small cell lung cancer (NSCLC) tumour bearing tissues were supplied by

Dr David Lewis and Professor Kevin Brindle, our collaborative partners at The University of Cambridge.

MR Imaging of tumour hypoxia

Hypoxia is critical in promoting genomic instability in tumours and determining therapeutic response, so

can drive the complex genetic heterogeneity observed in all human solid cancers. Mapping tumour oxygen

tensionandhypoxiacanhavesignificantimpactonpatientmanagementbethatthroughselectingappropriate

treatments or monitoring response. Current hypoxia assays involve biopsy and histological sampling, but these

are invasive and do not provide comprehensive tissue coverage. Imaging approaches are attractive in that

they are non-invasive, enable multiple measurements and allow whole tumour mapping. Oxygen-enhanced


magnetic resonance imaging (OE-MRI) is a promising technique for quantifying tissue oxygenation status and

tumour hypoxia, which has been developed as a cancer biomarker in Manchester.

Work led by Professor Kaye Williams and Dr James O’Connor is focussing on the biological validation of

quantitative OE-MRI measurements in multiple tumour models, including 786-O (Figure 3), SW620, U87 and

Calu6 xenografts. Initial studies have shown that OE-MRI measurements detect chronic hypoxia and when

combined with dynamic contrast enhanced MRI (DCE-MRI) can track evolution of tumour hypoxia and response

to hypoxia targeted agents and radiotherapy. Part of this work has been in collaboration with Dr Simon Robinson

at the Institute of Cancer Research. Ongoing work is looking at the relationship of MRI measurements to PET

tracers of hypoxia (18F-FAZA) and photoacoustic methods of imaging hypoxia, the latter in collaboration with

Dr Sarah Bohndiek in Cambridge. Evaluation of therapy induced responses and test-retest reproducibility has

begun in clinical studies in patients with rectal cancer and NSCLC.

Mapping and quantifying tumour heterogeneity

Most tumours demonstrate biological heterogeneity with variation in genomic features and local environmental

factors such as hypoxia, which can stimulate local genetic mutation and the evolution of treatment resistant

tumour cells. Regional variations in proliferation, cell death, metabolic activity, vascular structure and other

factorsarecommon. Imagingoffersawide rangeof tools toassessbothclonalandcellularheterogeneity

but extensive development and optimisation is required. Although imaging biomarkers of heterogeneity

can be associated with disease progression, therapeutic response and malignancy, information concerning

heterogeneity is rarely utilised and there is no consensus concerning the choice of descriptive metrics.

Manchester has developed heterogeneity metrics that clearly outperform conventional summary metrics in a

number of areas involving diagnosis, tumour grading and treatment response. Current work, led by Professor

Alan Jackson, focuses on developing the potential of imaging-based heterogeneity measures using both MRI

and PET tracers. Initial studies to statistically combine data are focussing on existing glioblastoma data sets with

anatomical,diffusionweightedanddynamiccontrastMRI.Theapproachwillthenbeextendedtoencompass

PETdata,evaluatedintissuesaffectedbyphysiologicalmotion.Neuro-oncologicalMRdatawillenableusto

validate and test our methods. Next, studies will integrate serial clinical imaging and biopsies (including liquid

biopsies) with the aim of detecting and unravelling response/resistance induced changes to both novel agents

and repurposed drugs. Immunohistochemical and genetic analysis - whole genome sequencing, whole exome


Figure 3: Combined OE-MRI and DCE-MRI tumour segmentation and relationship to pathology In panel a, OE-MRI and DCE-MRI data from a renal cancer 786-O xenograft are combined. Blue voxels have a ‘hypoxia’ signature and map spatially to the tumour region shown to be hypoxic on IHC staining of pimonidazole adduct formation (panel b). Yellow voxels (in panel a) map spatially to well perfused tumour regions as revealed by Hoechst 33342 staining.



sequencingandRNAsequencing-ofbiopsieswillbeusedtoqualifyimagingbiomarkerbasedclassifications,

in collaboration with Professor Richard Marais. The multi-dimensional data (genomic, automated microscopy-

image analysis and radiological images) will be integrated by developing a robust integrated database and

analysis pipeline with proper visualisation tools to give a systems view of cancer at diagnosis and as it evolves

in response to treatment.



Biobank building on success

The Manchester Cancer Research Centre Biobank was established in 2007

with the ultimate aim of making quality tissue collection and retrieval easier

for the researcher. There are a number of elements which are vital in building a

successful Biobank and the MCRC Biobank has approached each one carefully

to ensure that a robust infrastructure and service is provided to stakeholders

who wish to use biological samples for high quality cancer research.

The four key considerations when building a successful Biobank (Figure

1) include; compliance with the regulatory framework, which includes The

Human Tissue Act and Ethics Approval, ensuring adequate logistics for timely

procurement of specimens of a variety of types, quality sample collection by

following standard operating procedures and a robust informatics infrastructure

to ensure samples can be linked to clinical data and can be tracked and

traced appropriately.

Jane Rogan

Informatics Quality

RegulatoryFramework

Logistics

Figure 1: Key Elements of a Successful Biobank


The MCRC Biobank community consists of the core work team, which is

established under The Christie Division of Research, the Histology Core Facility

within the Cancer Research UK Manchester Institute and a cross-cutting team

ofclinicalstaff,suchassurgeons,pathologistsandoncologists,withoutwhom

the Biobank would not be able to function.

Since inception, the Biobank has proven its success in supporting research

within the MCRC and beyond. Samples have been collected from over 6500

patients and the Biobank has approved almost 100 Biobank applications to

use collected samples. To serve the Manchester cancer research community

as a whole, samples are collected across many solid tumour types. Figure

2 demonstrates the spread of solid tumour sample collection over the life

of the Biobank.

In addition to the solid tumour bank, the MCRC Biobank also has a haematological

malignancy arm, which collects blood and bone marrow from patients with

leukaemia and other blood disorders (see Figure 3). Although separately run

and managed through the CRUK MI histology core facility, it falls under the

MCRC Biobank research tissue bank ethics approval and access to samples is

facilitatedthroughaunifiedaccesspolicyforbothsolidandliquidtumours.

Evolutionofaflexiblemodel

In the seven years since the MCRC Biobank was established, it has responded

to research requirements by developing a flexible model to ensure that

researchers’ needs can be met. Originally set up with the premise that a six-

packof fixed and frozen tumour, normal andmatchedblood andurine from

patients undergoing surgery would be banked for future use, it soon became


Figure 2: Solid tumours Figure 3: Liquid tumours

Collection By Disease Group - Solid Tumours

Brain Breast Skin Colorectal

Upper GI Gynae Urology Lung Other

Collection By Disease Type - Haematological Malignancy

AML B-ALL MDS Other



apparent that this would only satisfy a proportion of research need. The Biobank was approached to facilitate

sample collection beyond this initial aim and it also became important to ensure that collected samples and

sample types were useful and being used.

To facilitate bespoke requests, the Biobank has had to respond rapidly to manage the logistical and ethical

challengesthiscanbring.Thefirstsignificantchangewastheshift frompurely retrospectivebiobankingto

more prospective sample collection, driven by both the requirement for samples which can only be collected

prospectivelyandtheneedtoensurefiniteresourceisusedasefficientlyaspossible.

Specific requests for samplesnow facilitated through theBiobank includecollectionof fresh tissue,which

requirescoordinationofstafftoensuresamplescanbedeliveredimmediatelytotheresearcherandthequality

of the sample can be maintained. This is often coupled with the need for consent to be taken to allow tissue

to be used for the creation of animal models of disease, a requirement under The Human Tissue Act. This

requires detailed planning on both the Biobank and research side where tumour size, type of media used and

cold ischaemia time all impact on the viability of the sample for its intended use.

To further meet research requirements, an update to the Biobank’s research tissue bank ethics approval now

allows a single consent to enable serial collection of samples, something which has facilitated research studies

involving the collection of blood from patients throughout the course of their treatment. The new forms also

allow the patient to be consented for collection of alternative, non-invasive sample types, such as ascites,

pleuralfluidandpluckedhair.

For each tailored requirement, the Biobank has to consider various elements which may impact the collection

and each condition can bring several different considerations. Table 1 demonstrates the various flexible

requirements that the MCRC Biobank now facilitates and the various considerations for each.



Requirement Considerations

Prospective Fresh Tissue• Availability of tissue• Staffavailableforsampledelivery• Media for keeping samples viable

Use for Animal Models• Specificconsentforanimalmodels• Size of tumour tissue

AlternativeSampleTypes(fluids,pluckedhair) • Routes / logistics of sample collection

Serial Blood Collection (including CTCs)• Biobank Technician presence in clinic • Oncologists willing to take patient consent

Past samples (e.g. pre-treatment/primary tumours)• Specificconsent• Requesting blocks from local hospitals

Samplingtumourindifferentareas • Further input from pathology

Clinical Trial Sample Collection• Space for sample storage• Differentprotocolsforeachtrial

Inadditiontocreatingaflexiblemodelforsamplecollection,theBiobankalsoappliesthesameethostodata

collection. This has been facilitated by obtaining a permission called Section 251 support from the Health

Research Authority, which allows linkage of large archival tissue sample cohorts, falling outside of the consent

provisions of The Human Tissue Act, to be married to clinical datasets. This enables follow-up and outcome

data to be linked to the tissue samples so that research looking at markers for survival and disease progression

can be carried out.

Added Value

In addition to its core work, in recent years the Biobank has also acted as a vehicle to deliver a number of

nationalresearchinitiatives,whichdemonstratetheeffectivenessoftheBiobanktodeliverlarge-scalesample

collection within the Manchester Cancer Research Centre.

Thisbegan inJuly2011withPhase1oftheCancerResearchUKStratifiedMedicineProgramme(SMP1),a

pilot study to demonstrate on a small scale how the NHS can provide molecular diagnosis for all cancer types

routinely. The MCRC Biobank was selected to act as one of seven Clinical Hubs to collect samples and data

frompatientsacrossfourtumourtypes.SectionsfromeachsamplecollectedweresenttoCardiffTechnical

Hubwhereaspecificpanelofuptosixgenespertumourtypewastested.Manchesterwasaconsistentlyhigh

recruitertoSMP1andwastheonlyClinicalHubtosignificantlyoverachieve;collectingsamplesfromnearly

1000 patients in less than two years.

TheBiobankisnowinvolvedinPhase2oftheStratifiedMedicineProgramme(SMP2),whichhasalungfocus,

and the Biobank are working closely with MCRC lung cancer researchers to deliver this. SMP2 will feed directly

into the National Lung Matrix trial which will be opening in 2015 and this will allow patients to access targeted

treatments specifically linked toanygenetic aberrations identifiedaspartof thegeneticpanel carriedout

through the programme.

Due to Manchester’s success in delivering SMP1, Cancer Research UK selected the Biobank to act as a centre

for the 100,000 Genomes pilot, a precursor to the Genomics England (GEL) 100,000 Genomes Project, a

government funded initiative aiming to sequence the genome of 100,000 NHS patients and their families in

cancer and rare diseases.

Table 1: Facilitating sample collection for a range of requirements



Being part of the pilot has enabled a strong working relationship to develop between the MCRC Biobank and

the Manchester Regional Genetics Service at St Mary’s Hospital, who have been responsible for the DNA

extraction of blood and tissue collected from patients and who have been running a parallel rare diseases pilot.

At the end of 2014, Central Manchester University Hospitals NHS Foundation Trust (CMFT) and The Christie

NHS Foundation Trust submitted a joint bid to become a Genomics Medicine Centre (GMC) for the 100,000

Genomes Project and were successfully selected in the first wave. CMFT will act as the overall lead for

Manchester and for rare diseases, with The Christie leading on the cancer element. It is anticipated that the

cancer sample collection will begin in May 2015.

In addition to the 100,000 Genomes Project and SMP, the Biobank is also facilitating sample collection

for a number of lung specific studies, including TRACERx, a mesothelioma bank called MesoBank and is

collaborating with the Manchester Respiratory and Allergy Biobank (MANRAB) to collect normal lung tissue for

non-cancer lung-related research.

Future Developments

The growth of the MCRC and the new MCRC building present a real opportunity for the Biobank to also grow and

develop further to meet the needs of researchers. 2015 will see the development of a new, more streamlined

AccessPolicy tocopemore readilywith thegrowingdemand for samplesand further staff recruitment to

ensure that the MCRC’s research objectives are not hindered by lack of resource for tissue collection in key

disease areas.

The Biobank will continue to work hard to its mission statement:

Facilitating high quality cancer research by bringing a flexible and committed approach to ethical sample and

data collection



Author Biographies

Caroline Dive is a Senior Group Leader at the CRUK Manchester Institute and

Professor of Pharmacology at The University of Manchester. After completing

her PhD studies in Cambridge, Caroline moved to Aston University’s School

of Pharmaceutical Sciences in Birmingham where she started her own group

studying mechanisms of drug induced tumour cell death. She then moved to

what became the Faculty of Life Sciences at The University of Manchester to

continue this research. Caroline was awarded a Lister Institute of Preventative

Medicine Research Fellowship before moving to the CRUK Manchester Institute

in 2003. Here she set up the Clinical and Experimental Pharmacology group

interfacing with the early clinical trials unit at The Christie.

Andrew Hughes is Chair in Cancer Experimental Therapeutics and Strategic

Director of the Experimental Therapeutics Unit at The Christie NHS Foundation

Trust. He graduated with a double first in Medical Sciences at Cambridge,

spending 3 years as a tutor in Physiology and Bye-fellow of Downing College,

Cambridge, whilst completing a PhD in Behavioural Neuroendocrinology

in the Department of Anatomy. Andrew subsequently practised General

Clinical Medicine in Manchester’s teaching hospitals in the UK, before joining

AstraZeneca in 1994. Until 2015 he held a dual appointment as Professor of

Translational Medicine at The University of Manchester and Head of Early

Clinical Oncology Development at AstraZeneca.

Jonathan Tugwood is Senior Translational Scientist in the Clinical and

Experimental Pharmacology (CEP) group, CRUK Manchester Institute.

Following a BSc in Biological Sciences at Birmingham University and a PhD in

Molecular Virology at Manchester University, he undertook post-doctoral

studies in embryonal genetics at Columbia University, New York. This was

followed by a post-doctoral position in Molecular Toxicology with ICI (now

AstraZeneca) at the Alderley Park site, which became a permanent team leader

role in 1991. Jonathan moved to AstraZeneca Pharmaceuticals in 1997 to join

the Global Safety Assessment function as a team leader, carrying out original

research in drug toxicology, and providing support for drug discovery and

development programmes. He joined CEP in 2012, and has responsibility for

theCEPbiomarkertrialsportfolio, includingoversightofthestaffdeveloping

new circulating biomarker assays and delivering biomarker data for CEP’s trials

and experimental medicine portfolio.

Andrew Hughes, Jonathan Tugwood, Caroline Dive, Matt Krebs, Emma Dean - Ambitious plans for Experimental Therapeutics - Page 8


Emma Dean is a clinical senior lecturer within the Institute of Cancer Sciences

at The University of Manchester and Honorary Consultant in Medical

OncologyatTheChristieNHSFoundationTrust.Shequalified inMedicineat

The University of Nottingham, graduating with a Bachelor degree in Medical

Sciences, Bachelor of Medicine and Bachelor of Surgery. After completing

general medical training, she took up a specialist post in Medical Oncology at

The Christie, Manchester. She was awarded a PhD in 2009 for research into

novel anti-cancer therapies that promote cancer cell death through a Cancer

Research UK Fellowship. Postgraduate research as a National Institute for

Health Research Clinical Lecturer focussed on early phase clinical trials using

novel targeted small molecule inhibitors, next generation chemotherapeutics,

and anti-angiogenics, either alone or in combination with licensed therapies

or radiotherapy. Her current research interest is first-in-human therapies in

medicaloncologywithaspecificinterestinmoleculartargetedapproaches.

Matthew Krebs is a clinical senior lecturer within the Institute of Cancer

Sciences at The University of Manchester. He completed his degree in Medicine

at The University of Leicester in 2001 and took opportunity to spend an

undergraduate elective period at the London Regional Cancer Centre, Ontario,

Canada. Following general medical training in Manchester he commenced

specialist training in Medical Oncology at The Christie NHS Foundation Trust in

2005. Matthew subsequently joined the Cancer Research UK/AstraZeneca PhD

Clinical Fellowship programme in November 2007 and was a clinical research

fellow within the Clinical and Experimental Pharmacology group at the Cancer

Research UK Manchester Institute. His research focuses on the isolation and

characterisation of circulating tumour cells from patients with lung cancer with

a view to developing these as predictive and/or pharmacodynamic biomarkers

in early phase clinical trials.

Tony Howell is Professor of Medical Oncology at The University of Manchester

and, along with Gareth Evans and Nigel Bundred, he leads the Nightingale Centre

and Genesis Prevention Centre at University Hospital of South Manchester

NHS Foundation Trust. He is the former Director of the Breakthrough Breast

Cancer Research Unit, and the Manchester Breast Centre. He trained at

Charing Cross Hospital, London and, after a period with the Medical Research

Council, moved to Birmingham and then took a post to lead Breast Medical

Oncology at The Christie NHS Foundation Trust in Manchester. Formerly

he was Chairman of the UK Breast Trials Organisation (UKCCCR), the British

Breast Group and the ATAC trial and, up until the end of 2007, was the Research

&DevelopmentDirectorofTheChristieNHSFoundationTrustandResearch

DirectoroftheGreaterManchester&CheshireCancerResearchNetwork.His

interests are the endocrine therapy and biology of the breast and breast cancer

with a particular interest in prevention. He has published over 480 papers mainly

in these areas.

Author Biographies

Tony Howell, Rob Clarke, Gareth Evans - Breast Cancer research at the Manchester Breast Centre - Page 14


Rob Clarke carried out undergraduate BSc studies in Biology at the University

of Sussex and the Université de Grenoble in France, graduating in 1987.

Following two and half years as a Research Assistant with Professor Potten at

the Paterson Institute for Cancer Research, his PhD studies investigated the

control of proliferation in the normal and neoplastic human mammary gland.

Subsequent post-doctoral training with Dr Liz Anderson was in the Clinical

Research Department of The Christie, Manchester. In 2001, he returned to The

University of Manchester as a Cancer Research UK Research Fellow, becoming

a Group Leader. Currently, he is Senior Lecturer and Deputy Director of the

Breakthrough Breast Cancer Research Unit in the University of Manchester’s

Institute of Cancer Sciences based at the Paterson Building.

D Gareth Evans has a national and international reputation in clinical and

research aspects of cancer genetics, particularly in neurofibromatosis and

breast cancer, and is Chairman of the NICE (National Institute for Clinical

Excellence) Familial Breast Cancer Guideline Development Group. He has

developed a clinical service for cancer genetics in the North West Region and

lectures within the UK and internationally on hereditary breast cancer and

cancer syndromes. He has also developed a regional training programme

for clinicians, nurses and genetic associates in breast cancer genetics, and

established a system for risk assessment and counselling for breast cancer in

Calman breast units.

Fiona Blackhall trained in Manchester and for two years in Toronto with Dr

Frances Shepherd. She was appointed Consultant Medical Oncologist at The

Christie NHS Foundation Trust in 2005, joining the Manchester Lung Group led

by Professor Nick Thatcher. She was awarded an Honorary Senior Lecturer role

at The University of Manchester in 2007. She is an active clinical trialist with a

focus on development of mechanism based therapies and has a major role in

biomarker research. She is Chair of the translational subgroup of the recently

established European Thoracic Oncology Platform, a member of the NCRI

Lung Clinical Studies Group and leads the MCRC lung cancer research team.


Caroline Dive, Fiona Blackhall, Phil Crosbie, Rajesh Shah - Circulating tumour cell (CTC) research in early stage, resectable non-small cell lung cancer (NSCLC) - Page 18


Phil Crosbie is a Consultant Respiratory Physician based at the University

Hospital of South Manchester with a special interest in lung cancer. He started

his training in Edinburgh before moving to Manchester where he completed

a PhD exploring the molecular epidemiology of lung cancer at The University

of Manchester, prior to taking up an NIHR Clinical Lectureship. He delivers

interventional bronchoscopy services both at UHSM and The Christie. His

current research interests include the early detection/staging of lung cancer

and the study of circulating biomarkers and biology of circulating tumour cells

in early stage disease. His laboratory work is based in Professor Caroline Dive’s

CEP group at the CRUK Manchester Institute.

Claudia Wellbrock is a Reader in the Faculty of Life Sciences at The University

of Manchester. She received an MSc in Chemistry from the University of

Wuerzburg, Germany and during her PhD project at the Max Planck Institute

of Biochemistry in Wuerzburg studied the oncogenic function of receptor

tyrosine kinases. She continued with postdoctoral studies at the University of

Wuerzburg focusing on the signal transduction pathways involved in pigment-

cell transformation and melanoma development. In 2002, she joined the

laboratory of Richard Marais at the Institute of Cancer Research in London, UK,

where she investigated the role of BRAF in the initiation and development of

melanoma. She moved to The University of Manchester in September 2007

and her current work aims to understand the crosstalk between particular

cellular signalling cascades in melanoma initiation and progression in order to

identify new targets for cancer therapy.

Donald Ogilvie heads the Drug Discovery Unit at the MCRC. He joined the

Cancer Research UK Manchester Institute as a senior group leader in February

2009 after a twenty year career in the pharmaceutical industry. Donald obtained

anMAinBiochemistryatOxfordin1980beforeworkingattheJohnRadcliffe

Hospital for eight years on the role of proteases in breast cancer then inherited

connective tissue disorders. The latter was the basis of his D.Phil degree. In

1988 he joined ICI, which subsequently became Zeneca then AstraZeneca.

For most of his industrial career, Donald worked on cancer drug discovery and

early clinical development and he was directly responsible for the delivery of ten

novel cancer development compounds, several of which have progressed to

PhaseII&IIIclinicaltrials.

Author Biographies

Claudia Wellbrock - Heterogeneity in Melanoma - Page 24

Allan Jordan, Ian Waddell and Donald Ogilvie - Translating Cancer Biology into Novel Therapeutics in the Manchester Cancer Research Centre - Page 26


Allan Jordan joined the Drug Discovery Unit in July 2009 as Head of Chemistry.

After gaining a BSc in Chemistry from UMIST in 1993 and a short spell as a

teaching assistant in Arizona, he returned to UMIST to conduct post-graduate

research into anticancer natural products. After post-doctoral work at the

University of Reading, he joined RiboTargets in Cambridge (now Vernalis) where

he worked on a number of therapeutic areas at various stages of the research

pipeline. Alongside involvement in a number of oncology programmes,

ultimately leading to the clinical evaluation of Hsp90 inhibitors in conjunction

with Novartis, he became involved in CNS research programmes where he was

a project leader on a GPCR drug discovery programme and was also involved in

the management of Vernalis’ clinical programme for Parkinson’s disease.

Ian Waddell joined the Drug Discovery Unit in June 2011 as Head of Biology.

He gained a BSc and PhD in Biochemistry at the University of Dundee. After a

short spell as a post-doctoral research associate, he spent 5 years as a lecturer

in Molecular Medicine in the Department of Child Health at Ninewells Hospital,

before joining Zeneca in 1994. His interest in Oncology began when he led the

Cachexia team looking at preventing the skeletal muscle wasting associated

with pancreatic cancer.

Tim Somervaille trained in Medicine at St Mary’s Hospital Medical School (now

part of Imperial College London) and University College London. Following

postgraduate training in General Medicine in London, he underwent specialist

haematology training at UCL where he also studied for a PhD as a Medical

Research Council Clinical Training Fellow in Professor Asim Khwaja’s laboratory.

He then spent four years undertaking postdoctoral studies in leukaemia in

Michael Cleary’s laboratory at Stanford University as a Leukaemia Research

Fund Senior Clinical Fellow. He now leads the Leukaemia Biology group at the

Cancer Research UK Manchester Institute and is also Honorary Consultant in

Haematology at The Christie NHS Foundation Trust.


Tim Somervaille - Collaboration pays dividends for leukaemia research - Page 32


Gordon Jayson is Professor of Medical Oncology at The University of

Manchester and leads the glycoangiogenesis research within the Institute of

CancerSciences.Hequalified inMedicineat theUniversityofOxfordbefore

undertaking medical and oncology training in Manchester at The Christie.

Following a PhD in heparan sulfate biology, Gordon conducts research that

aims to translate new data and understanding of heparan sulfate biology gained

from fundamental research into the clinic.

Tim Illidge is Professor of Targeted Therapy and Oncology at The University

of Manchester. He is also Honorary Consultant in Oncology at The Christie,

with a clinical interest in the management of lymphoma. Tim completed his

undergraduate degree at London University, before studying medicine at

Guy’s Hospital Medical School and then completing a PhD at the University

of Southampton. Following this, he completed research fellowships in

Southampton and at Stanford University in California. Currently Tim is chair

of the National Cancer Research Institute (NCRI) Clinical and Translational

Radiotherapy (CTRad) group and serves within national and international

Lymphoma groups.

Nick Slevin is Director of Networked Services at The Christie and Honorary

ProfessorofClinicalOncology atTheUniversityofManchester.Hequalified

in medicine from Birmingham in 1978 and completed postgraduate training

in General Medicine in South Warwickshire and New Zealand. Nick trained

in Oncology in Nottingham and Manchester and has specialised in the non-

surgicalmanagementofheadandneckcancer since1988.Hewas thefirst

Chair of the National Cancer Research Institute Head and Neck Group and the

RoyalCollegeofRadiologists’firstleadoftheheadandneckelectronicnetwork.

Author Biographies

Gordon Jayson - Ovarian cancer and angiogenesis - Page 34

Tim Illidge, Catharine West and Nick Slevin - Key role for Radiotherapy in personalised approach to cancer treatment- Page 38


Catharine West leads the Translational Radiobiology group at The University

of Manchester. She studied Biology as an undergraduate at York University and

Radiobiology as a postgraduate at the Institute of Cancer Research, Sutton.

After postdoctoral work at the University of Rochester Cancer Centre, New

York, she joined the Paterson Institute for Cancer Research in 1986, and in

2002, joined The University of Manchester.

James O’Connor read Medicine at Magdalene College, University of

Cambridge and at the Royal Free Hospital, London, graduating with an MA in

History and Philosophy of Science and with the MB, BS degrees. After MRCS,

he began specialist training on the Manchester Radiology Training Scheme

in September 2004. He joined the Imaging Sciences department at The

University of Manchester in 2005 initially studying for a PhD, developing MR

and CT imaging biomarkers of tumour microvascular heterogeneity. This was

funded by a Cancer Research UK Clinical Research Training Fellowship. Post-

doctoral research was as an NIHR and Wellcome Trust funded Clinical Lecturer

in Radiology, from 2010. He was appointed Senior Lecturer with an Honorary

Consultant Radiologist post at The Christie in January 2012 and the following

year began a four-year intermediate Fellowship with a Cancer Research UK

Clinician Scientist Award.

Adam McMahon studied at The University of Oxford, The University of Bristol

and Dalhousie University in Canada, where he gained a BA (Hons) in Chemistry,

an MSc in Analytical Chemistry and a PhD in Chemistry. In 1988 he became

Harwell-Wolfson Research Fellow, based at the UKAEA’s Harwell Laboratory and

Wolfson College, Oxford. Then in 1991 he became Manager for Research and

Development in the AEA Technology’s Analytical Sciences Centre at Harwell.

Before joining the Wolfson Molecular Imaging Centre in January 2005, he

worked for 12 years as a Senior Lecturer in Chemistry and Analytical Chemistry

Section Leader at Manchester Metropolitan University.


James O’Connor, Adam McMahon, Geoff Parker, Kaye Williams and Alan Jackson - Imaging Science research at the MCRC - Page 42


Geoff Parker leads the QBI Lab and the Unit of Neuroimaging and Tractography

(UNIT) at The University of Manchester. He is also Director of a University of

Manchester spin out company, BiOxyDyn Limited.

Alan Jackson joined The University of Manchester in 1993 and was appointed

Professor of Neuroradiology in the Imaging Sciences Group within the Faculty

of Human and Medical Sciences at The University of Manchester in 1995. Prior

to this, he was a full-time NHS clinical neuroradiologist at the Manchester Royal

Infirmary. Alan holds honorary chairs inNeuroimaging at theUniversities of

Liverpool and Bangor and is also an honorary clinical consultant at the Salford

HospitalsNHSTrustandtheManchesterRoyalInfirmary.

Kaye Williams received a BSc in Molecular Biology from The University of

Manchester and a PhD from the Paterson Institute for Cancer Research.

Following Research Associate and Research Fellow positions within the

Experimental Oncology Group of the School of Pharmacy and Pharmaceutical

Sciences, headed by Professor Ian Stratford, she was awarded the British

Association for Cancer Research/AstraZeneca Frank Rose Young Scientist

Award in 2005. In January 2006 Kaye was appointed Senior Lecturer within

the School of Pharmacy, became Reader in 2010, and in 2012 was promoted

to Chair in Experimental Therapeutics and Imaging. She currently heads the

Hypoxia and Therapeutics group and is the MCRC lead for Preclinical Imaging.

Author Biographies



Jane Rogan is Business Manager of the MCRC Biobank and has a wider role at

The Christie NHS Foundation Trust as HTA Designated Individual for research.

Jane has extensive experience of human tissue research and its accompanying

regulation and has been involved in tissue banking and its related governance

for ten years. Jane has a Biological Sciences undergraduate degree from The

UniversityofBirminghamandanMBAfromHuddersfieldUniversityBusiness

School. She is currently studying for an MSc in Healthcare Leadership as part of

the NHS Leadership Academy Elizabeth Garrett Anderson Programme.

Noel Clarke is a Consultant Urological Surgeon at The Christie and Salford

Royal Hospitals in Manchester and Professor of Urological Oncology at The

UniversityofManchester. HequalifiedinmedicineatCharingCrossHospital,

London, in 1981 and gained full accreditation as a Urological Surgeon in 1993.

Noel is Chairman of the National Cancer Research Institute (NCRI) Prostate

Clinical Studies Group, Chairs the European Organisation for Research and

Treatment of Cancer (EORTC) Prostate Disease Orientated Group and is Chair

of the Greater Manchester and Cheshire Urology Network Clinical Studies

Group. He directs the Genito-Urinary (GU) research group and is the Principal

Investigator of the Manchester arm of the Medical Research Council (MRC)

Northern Prostate Cancer Collaborative. Noel’s research has focused on

cancer stem cell biology and the pathophysiology of metastatic behaviour, with

translational studies directed towards analysis of new biomarkers, advanced

cancer imaging and the evaluation of novel therapies.

Jane Rogan - Biobank building on success - Page 48

Manchester Cancer Research CentreThe University of Manchester

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