Centre for Cancer Stem Cells and Ageing

Led by Professor Christopher Heeschen

Why we focus on Cancer, Stem Cells and Ageing

Stem Cells & Cancer

With the availability of ever more sophisticated model systems and technologies it has now become evident that cancers are driven by phenotypic and functional heterogeneity and that striking plasticity exists within each subclone. So-called cancer stem cells are responsible for this intraclonal heterogeneity (Figure 1).

Cancer stem cells represent a subset of cancer cells, for which we and other have provided conclusive evidence down to the single-cell level that they represent the root of the disease by giving rise to all differentiated progenies within each cancer subclone. Even more importantly, these cells are driving the metastatic behaviour of many cancers and represent an important source for disease relapse. Thus, cancer stem cells should signify a crucial component for any novel treatment approach.

CSC_concept
Figure 1 – Cancer stem cell concept and cancer evolution

Cancer & Ageing

In the UK, 155,000 people aged 70+ years are diagnosed with cancer every year representing 50% of all cancer diagnoses, a number likely to rise as the population ages. Survival rates for older cancer patients lag behind younger patients with the same cancers. We now face new problems in understanding the biology of older people who develop cancer, which also includes, but is not limited to important co-morbidities such as diabetes and metabolic syndrome.

Compelling new evidence from the Barts Cancer Institute (BCI) indicates that epigenetic controls are fundamental to many molecular switches between senescence and immortalization. Furthermore, DNA methylation is a central mechanism underpinning genome stability and gene expression. Many other hallmarks of ageing have also been implicated as also important determinants of cancer initiation and/or progression (Figure 2). Therefore, cancer needs to be studied in the appropriate context, but most of our current cancer models are lacking important aspects of ageing, co-morbidities and subsequent changes to the tumour microenvironment.

Ageing

Figure 2 – The Hallmarks of Ageing (modified from Lopez-Otin et al. Cell 2013)

What we do

The BCI will pioneer a Centre for Cancer, Stem Cell & Ageing that spans both molecular and patient biology to address the twin issues of cancer and ageing in cancer (stem) cells and in people. Building on our established strength in stem cell biology, we will further expand our laboratory programme to important aspects of our ageing patient population including age-related co-morbidities.

Our programme will join efforts with established research strands at BCI focusing on DNA repair and genome stability, epigenetics and senescence, as well as ageing and immune function. In collaboration with our Clinical Trial partners at Brighton and Sussex Medical School, who have an established a clinical research programme in older patients with cancer, and with Attilla Lorincz (Molecular Epidemiology, Wolfson Institute of Preventive Medicine), we are in a position to apply newly developed quantitative tools for DNA methylation analyses, such as pyrosequencing and deep sequencing of methylomes, coupled with bioinformatics to determine the levels of tissue genome plasticity and the role of driver epigenetic mutations in diverse cancers.


Who does the research

→  Click here for BCI senior researchers working on ageing and senescence

Centre for Tumour Biology

Led by Professor Sir Nicholas Wright

Our centre has 45 or more researchers, working on different aspects of the biology of transformed cells or the stromal cells found in neoplastic foci. We bring together individuals with a diverse range of expertise in cell biology, molecular biology and pathology to form a synergistic approach to complex biological problems.

Our unifying interest is in understanding the cellular and molecular events which drive tumour progression to the malignant phenotype. We have a particular interest in understanding the nature of the “cross-talk” between epithelial cancer cells and their stromal partners during cancer evolution.

The centre is based around an open-plan laboratory to maximise the opportunity for collaboration and interaction between the different groups and group members.

We bring together research scientists and clinicians to work on the research problems, with a focus always on the validation of ideas and observations in clinically-derived material, to ensure that bench-work is oriented toward understanding a “real” phenomenon.

Please click here for profiles of staff in the Centre for Tumour Biology

Life in the Centre

Follow the links below to get a sense of what life is like for researchers in our centre:

rachel-barrow

Rachel Barrow
PhD Researcher

mike-allen

Michael Allen
Post Doctoral Researcher

 

Facilities

Here at the Centre for Tumour Biology we are responsible for the Zeiss 510 and the Zeiss 710 confocal microscopes, which are used in the imaging centre and greatly aid our work.

Major Projects

  • February 2011 - February 2014. Medical Research Council Project Grant:  £460,000 (Professor Kairbaan Hodivala-Dilke)
  • October 2010 (duration 60 months). Modelling the stromal regulation of tumour angiogenesis. Cancer Research Programme Grant: £3.1M (Professor Kairbaan Hodivala-Dilke and Professor Louise Jones)
  • Start 2010 (duration 60 months). Establishment of the BCC Breast Cancer Tissue Bank, (joint with Leeds, Dundee and Nottingham) Breast Cancer Campaign. £3.5M total, £1.1M to Barts. (Professor Louise Jones)

Centre for Haemato-Oncology

Led by Professor John Gribben

This Centre seeks to understand the molecular basis for lymphoma, leukaemia and myeloma to identify targets for novel targeted therapies and to identify biomarkers of prognosis and response to treatment. We also seek to understand the impact of the tumour microenvironment on malignant cell survival and resistance to therapy. A long-standing strength has been the translational components with strong links to the clinic through clinical senior lecturers and clinical research fellowships and high enrolment of patients in clinical trials.  Our main research interests are:

  • Cancer Immunotherapy:
    The aim is to develop immunotherapy approaches for the treatment of cancer, including stem cell transplantation; and to identify tumour antigens.
  • Applied Haemato-Oncology Group:
    The aim is to characterise the molecular signature of lymphomas to identify recurrent genomic and expression changes within these lymphomas to guide treatment selection.
  • Cancer Genomics:
    The aim is to understand the key genetic events in malignant transformation through molecular cytogenetics, SNP genotyping approaches and high throughput genomic sequencing.
  • Clinical Cancer Pharmacology:
    We conduct pharmacodynamic and pharmacokinetic studies of cytotoxic agents to develop and test new agents in the laboratory and in clinical trials. The goal is to optimise the use of chemotherapy drugs through a better understanding of their molecular and clinical pharmacology.

Please click here for profiles of staff in the Centre for Haemato-Oncology

Life in the Centre

Follow the links below to get a sense of what life is like for researchers in our centre:

aine-mccarthy

Aine McCarthy
PhD Researcher

essam-ghazaly

Essam Ghazaly Kerwash
Postdoctoral Researcher

Facilities

  • Affymetrix array facility
  • 454 (Roche) next generation sequencer
  • Ariol imaging system and software
  • Mass Spectrometry expertise within Centre
  • Haematological Malignancy Cell Storage Facility and HTA-Accredited Biobank

Centre for Molecular Oncology

Led by Professor Nick Lemoine

The Centre for Molecular Oncology, led by Professor Nick Lemoine, is the largest centre in the Institute, with nearly 70 staff and over a dozen group leaders. Our research uses novel molecular techniques to improve the diagnosis and treatment of cancer, focusing predominantly on pancreatic, genitourinary and gynaecological cancers, and is also involved in the development of novel cutting edge tumour imaging techniques. It is a world-leader in the field of cancer gene therapy and has close links to the departments of Solid Tumour Oncology, Gynaecological Oncology and Nuclear Medicine at St Bartholomew’s Hospital.

Research is carried out in three major areas:

  • Molecular pathology: identifying novel biomarkers to improve the diagnosis of pancreatic, prostate and lung cancers and to allow better prediction of both progression and prognosis.
  • Gene therapy: developing new mutant viruses that selectively replicate in and kill cancer cells.
  • Molecular imaging: developing novel radionuclides to improve both imaging and treatment of cancer.

Please click here for profiles of staff in the Centre for Molecular Oncology

Life in the Centre

Follow the links below to get a sense of what life is like for researchers in our centre:

lynsey-whilding

Lynsey Whilding
PhD Researcher

lara-boyd

Lara Boyd
Postdoctoral Researcher

Facilities

Pre-clinical imaging:

  • IVIS bioluminescence and fluorescence imager
  • Small animal SPECT-CT
  • Small animal PET-CT

Molecular Pathology:

  • Fully equipped molecular pathology laboratory working to GCP with laser capture microdissection capability and a fully automated Ventana IHC system.

Results and Discoveries

Molecular pathology of pancreatic, prostate and lung cancers

  • First genome-wide DNA copy number analysis in pancreatic cancer [Link]
  • First proof of concept study which demonstrated that signatures of pancreatic cancer can be detected in urine [Link]
  • First description of the role of S100 proteins in pancreatic cancer aetiology and progression [Link]
  • Description of loss of ASS expression in mesothelioma as a biomarker for sensitivity to arginine deprivation [Link]– this led to the opening of the phase I/II ADAM trial (ADI-PEG in Pleural Mesothelioma) in 2011.
  • First description of DNA polymerases as potential targets for tumours lacking mismatch repair genes MSH2 and MLH1 via synthetic lethality screening [Link]
  • First description of ability of androgens to induce prostate cancer TMPRSS2:ERG fusions in non-malignant prostate cells [Link]
  • First comparative analysis of genetic alterations in Chinese and Western prostate cancers [Link]
  • Contribution to international consortium to identify seven new prostate cancer susceptibility loci using GWAS [Link]

Gene therapy

  • First description of the importance of E3 region in activity of oncolytic adenoviruses in immunocompetent cancer models [Link]
  • Identification of role of CEACAM6 in modifying adenovirus transport [Link]
  • Description of the importance of host cell DNA damage responses in adenovirus activity [Link]

Molecular imaging

  • Opening of Cancer Research UK phase I trial of [F-18] Demobesin-4 PET imaging in prostate cancer (2010)
  • Description of the value of [F-18] FDG-PET in monitoring response to treatment in locally advanced breast cancer [Link]
  • First publication on how to conjugate chelating agents to peptides for radiolabelling and imaging [Link]

Centre for Experimental Cancer Medicine

Led by Professor Peter Schmid

The Centre provides design and management support for all trials in cancer patients including national, pharmaceutical and investigator-led studies. We have over 120 trials open at any one time, and recruit around 600 patients into studies every year.  We are supported by a £2M grant from Cancer Research UK and the Department of Health to undertake early phase (phase I/II) clinical trials. We focus particularly on biological therapies including antibodies, viral gene therapies and cell-based therapies.

Incorporated into the Centre is the Orchid Clinical Trials Unit, which is a team supported by the Orchid Charity and focuses on hypothesis-based phase II clinical trials in patients with prostate, testis and penile cancers.

The North-East London National Cancer Research Network is affiliated to the Centre and receives funding from the NIHR to provide research nurses, trial coordinators and data managers for randomised clinical trials across the network in North-East London.

Please click here for profiles of staff in the Centre for Experimental Cancer Medicine.

Life in the Centre

Follow the links below to get a sense of what life is like for researchers in our centre:

marita-marshall

Marita Marshall
Senior Clinical Trials Coordinator

sonya-mash

Sonya Mash
Research Nurse

 

Facilities

The Centre has offices both in Charterhouse Square and at St Bartholomew’s Hospital, as our staff spend much of their day with trial patients.

The trial facilities are integral to the brand-new Barts Cancer Centre, and study patients can be accommodated either as day-case or in-patients in state-of-the-art wards supported by a multidisciplinary Hospital Trust. The Cancer Centre includes world-class imaging facilities (64-slice Time of Flight PET/CT, 3T MRI etc) and advanced radiotherapy technology (Cyberknife, IMRT/IGRT).

Staff

The Centre offers support for clinical trials at all stages:

Biostatistics Support to assist in the optimal design of studies as well as subsequent management and interpretation of data.

Quality Assurance Management for the development, maintenance and continuous improvement of Quality Management systems (Standard Operating Procedures etc), staff training, liaison with Research and Development to ensure regulatory compliance, monitoring and audit of trials.

Clinical Trials Coordinators for management of the clinical trial portfolio, development and maintenance of central and study site files for ongoing clinical trials; preparation of  protocols, study documents, study reports and related regulatory submissions; and coordination of all pre-initiation administrative activities, as well as preparation of study-specific tools

Research Pharmacist who is responsible for all oncology clinical trials, and maintains the treatment protocol binders, supports staff in the preparation of study documentation.

Research Nurses who work with tumour-specific Multi-Disciplinary Teams to increase recruitment of patients into trials, and are involved in the management of patients and trial data.

Database Programmers and Administrators for the development and programming of clinical trials databases, including database set-up, eCRF generation and data analysis.

Results and Discoveries

Clinical trials infrastructure and governance:

We ensure that investigators have a completely consistent process for the establishment of all clinical trials, from phase I to phase III/IV. We can take proposals all the way from initial idea, through funding application, trial initiation and set-up, to trial completion and data analysis.

The Centre has a good record of MHRA inspections, and the Centre and its Tissue Bank were highly commended by the Human Tissue Authority. In addition, JACIE (Joint Accreditation Committee of the ISCT and EBMT) has not only accredited Barts as a centre for bone marrow transplantation, but also noted an ‘unparalleled’ level of research excellence in the field of transplantation.


Increasing recruitment and increasing the number of open trials:

There are currently over 120 cancer trials open to recruitment and around 600 patients are recruited into studies each year. This means that 1 in 5 of our cancer patients are now able to participate in a clinical trial, and we aim to increase this still further.


Investigator-initiated academic studies:

A series of investigator-led, academically funded studies has been initiated over the past 4 years, including DEPICT, ADAM, DB4 and MARALL, all funded by Cancer Research UK, and CNTO328, funded by the MRC.

ADAM is an excellent example of true translational research: the pre-clinical laboratory data underpinning the trial has been generated by Dr Peter Szlosarek as part of his CR-UK Clinician Scientist Fellowship and the trial funding is provided by a separate CTAAC grant, with collaboration from Polaris Pharmaceuticals.

COSAK (cediranib and saracatinib in renal cancer) is another example of a CTAAC-funded phase II study that was developed and led from this Centre.


Phase I studies:

In 2010 four phase I trials opened:
A first-in-man study of an Aurora kinase B inhibitor
A study of a Notch inhibitor in pancreatic cancer
A study combining dovitinib and everolimus. in renal cancer
A phase I trial of elacytarabine in relapsed AML


Imaging:

Imaging is a core strength of the Centre, which is equipped with state of the art clinical imaging technology to complement the leading edge facilities for preclinical imaging in the Centre for Molecular Oncology & Imaging. We are presently running a Positron Emission Tomography (PET) scanning study with a demobesin-4 probe developed in house in patients with advanced prostate cancer, funded by Cancer Research UK’s New Agents Committee. Another study, run in collaboration with the Cambridge ECMC is defining the FDG-PET parameters for response and non-response in relapsed ovarian cancer.