Centre for Stem Cells in Cancer & Ageing

Stem Cells in Cancer

The BCI pioneers a Centre for Stem Cells in Cancer & 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 interdisciplinary and complementary research programme integrates CSC biology with other BCI groups working on tumour initiation, the microenvironment & inflammation, stem cell biology, drug discovery, and early clinical trials (see below). Our work funded by the ERC advanced investigator grant over the past 5 years has contributed to an improved understanding of CSC biology and function, and set the stage for comprehensive characterisation of CSCs and their microenvironment.

Our interest in using novel technologies to foster diagnosis and treatment of patients with cancer has lead to collaborations with bioengineers at QMUL and beyond (e.g. nanoparticles, microfluidics, bioreactors, lab-on-a-chip), including translational projects with Physician-Scientists at the Barts NHS Trust. Our CSC-centred drug response screening platform ScanCSCTM and its further evolution provides a strong basis for precision medicine approaches with this support.

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 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.

Group Leaders in the Centre

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Life in the Centre

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Results & Discoveries

Papers

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Centre for Tumour Biology

Our centre's researchers work 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.

Group Leaders in the Centre

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Life in the Centre

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Results and Discoveries

Recent publications include:

Significant discoveries

  • The importance of dose - low-doses of anti-cancer drug cilengitide promotes tumour growth. PMID: 19305413

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Centre for Molecular Oncology

The main goal of our centre is to use our multi-disciplinary expertise in the molecular mechanisms of cancer to develop novel biomarkers and therapies that will improve outcomes for cancer patients.

Our themes include:

Group Leaders in the Centre

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Life In The Centre

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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]

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Centre for Haemato-Oncology

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.
  • Leukaemia Biology:
    Our research focuses on elucidating the biology of leukaemia initiating cells (LIC’s). By improving our understanding of the cellular basis of leukaemia initiation and maintenance we aim to shed light on how malignant growth is sustained in leukaemia and how this related to tumour recurrence following therapeutic intervention. These insights will ultimately inform the development of effective therapeutic approaches that can improve patient survival rates.

Group Leaders in the Centre

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Life In The Centre

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Results & Discoveries

Epigenetics

  • Discovered new functions of 5-hydroxymethylcytosine and pioneered the field of this novel epigenetic modification. PMID: 21460836
  • Identified major reprogramming events in embryonic stem cells in the ground state pluripotency. PMID: 23850245

Cell Signalling

  • The tumour microenvironment modulates the ability of PI3K inhibitors to induce apoptosis in cancer cells. PMID: 24648465
  • Environmental stress modulates the activity of cancer signalling networks. PMID: 24425749
  • A novel MS-based assay predicts responses of tumour cells to new cancer drugs. PMID: 23628362
  • A new computational method to analyse MS data identifies the most frequently over-activated kinases in primary leukaemia cells and predicts reponses to a PI3K inhibitor. PMID: 23330613

Precision Medicine

  • Landscape profile of Follicular Lymphoma genome. PMID: 24362818
  • Common progenitor population model of Follicular Lymphoma evolution. Blood, JCO
  • Inherited CEBPA mutations in Acute Myeloid Leukaemia. NEJM

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Centre for Experimental Cancer Medicine

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.

Group Leaders in the Centre

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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. {tab 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.

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