Research Oncology
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The Section of Research Oncology has as a central albeit non-exclusive theme of the pathobiology of breast cancer. Substantial activity surrounds cellular, genetic and proteomic studies on patient breast tumour samples, as well as exploitation of the derived data in the form of basic biological insights and (immuno) therapies. Additional areas of research strength are in novel imaging techniques, pathophysiology of lymphoedema, cancer outcomes and global oncopolicy.
Work of the Section includes:
·Breast Cancer Biology Group
·Breakthrough Breast Cancer Research Unit
·Breast Pathology Research Group
·Breast Cancer Stem Cell Biology Group
·Breast Cancer Surgical Group
·Epidemiology & Oncopolicy Group
·Phase 1 Trials
Andrew Tutt is a Consultant Clinical Oncologist and Director of the Breakthrough Breast Cancer Research Unit and a Professor of Oncology at King's College London. After training at the Royal Marsden Hospital, he worked with Professor Alan Ashworth at the Institute of Cancer Research, where he described the DNA repair functions of the BRCA2 breast cancer predisposition gene. He practises clinical oncology at Guy's Hospital and has developed a translational clinical trial programme focusing on cancers associated with functional deficiencies in BRCA1 and BRCA2. His interests involve the discovery of novel therapies in BRCA1/BRCA2-associated cancers and ER/HER2-negative/basal-like breast cancers—including the identification of poly(ADP-ribose) polymerase (PARP) as an exciting new target for therapy in these areas. He is chief investigator for the international BRCA and Triple Negative Breast Cancer Trials (TNT) and the phase II ICEBERG proof of concept trials of PARP inhibition with Olaparib in BRCA1 and BRCA2 carriers. He leads a neo-adjuvant trial initiative for Triple Negative Breast Cancer in Breast International Group Neo-BIG program. Dr Tutt's laboratory research interests focus on the identification and validation of potential treatment targets and biomarkers for women with Triple Negative Breast Cancer.
The Mammary stem cell biology group focuses on characterization of normal and malignant mammary stem cells in order to elucidate their role in cancer initiation and progression.
Developing an experimental framework appropriate for the study of stem cells of human origin is one of the priorities of the group and an ongoing effort. Novel experimental systems are employed to understand the molecular mechanisms that govern cell fate decisions and to identify defects in these mechanisms that can lead to transformation. The ultimate goal of these studies is to develop clinical applications based on stem cell biology concepts and to explore their translational potential in cancer diagnosis, prognostication, therapy and
prevention.
The CAR mechanics lab is focussed upon development of novel genetic strategies to target T-cell specificity against diverse malignancies. The approach we use entails the construction of cDNAs that encode for fusions known as Chimeric Antigen Receptors (CARs). These molecules couple the ability to target native tumour antigens to delivery of a tailored T-cell activating signal. Delivery to polyclonal peripheral blood T-cells is achieved using retroviral or lentiviral vectors. In a parallel theme, we are developing systems to target other lymphoid cell populations against cancer, including natural killer and gamma delta T-cells. Our first clinical trial of CAR-based immunotherapy is scheduled for 2012 and will involve the treatment of patients with squamous cell carcinoma of head and neck.
Recent Publications:
1. Maher J, Brentjens RJ, Gunset G, Riviere I, Sadelain M (2002) Human T lymphocyte cytotoxicity and proliferation directed by a single chimeric TCR/ CD28 receptor. Nature Biotechnology 20: 70-75. http://www.ncbi.nlm.nih.gov/pubmed/11753365
2. Maher J and Davies ET (2004). Targeting cytotoxic T-lymphocytes for cancer immunotherapy. British Journal of Cancer 91, 817-821. http://www.ncbi.nlm.nih.gov/pubmed/15266309
3. Lo AS, Gorak-Stolinska P, Bachy V, Ibrahim MA, Kemeny DM, Maher J (2007) Modulation of dendritic cell differentiation by colony-stimulating factor-1: role of phosphatidylinositol 3'-kinase and delayed caspase activation. Journal of Leukocyte Biology 82: 1446-54. http://www.ncbi.nlm.nih.gov/pubmed/17855501
4. Lo A, Taylor J, Farzaneh F, Kemeny DM, Dibb NJ, Maher J (2008) Harnessing the tumour-derived cytokine, colony-stimulating factor-1, to co-stimulate T-cell growth and activation. Molecular Immunology 45: 1276-87. http://www.ncbi.nlm.nih.gov/pubmed/17950877
5. Wilkie S, Picco G, Foster J, Davies DM, Julien S, Cooper L, Arif S, Mather SJ, Taylor-Papadimitriou J, Burchell JM, Maher J (2008) Re-targeting of human T-cells to tumour-associated MUC1 – the evolution of a chimeric antigen receptor. Journal of Immunology 180: 4901-9. http://www.ncbi.nlm.nih.gov/pubmed/18354214
6. Maher J, Wilkie S (2009) CAR mechanics: Driving T-cells into the MUC of Cancer. Cancer Research 69: 4559-62. http://www.ncbi.nlm.nih.gov/pubmed/19487277
7. Davies DM, Maher J (2010) Adoptive T-cell immunotherapy of cancer using chimeric antigen receptor-grafted T-cells. Arch Immunol Ther Exp. 58: 165-178. http://www.ncbi.nlm.nih.gov/pubmed/20373147
8. Wilkie S, Burbridge S, Chiapero-Stanke L, Parente-Pereira AC, Cleary S, van der Stegen JC, Spicer J, Davies DM, Maher J (2010) Selective expansion of chimeric antigen receptor-targeted T-cells with potent effector function using interleukin-4. Journal of Biological Chemistry. 285: 25538-44. http://www.ncbi.nlm.nih.gov/pubmed/20562098
9. Parente-Pereira AC, Burnet J, Ellison D, Foster J, Davies DM, van der Stegen C, Burbridge S, Chiapero-Stanke L, Wilkie S, Mather S, Maher J. (2011) Trafficking of CAR-engineered human T-cells following regional or systemic adoptive transfer in SCID Beige mice. Journal of Clinical Immunology. In press. http://www.ncbi.nlm.nih.gov/pubmed/21505816
two molecules, MUC1 and JARID1B/KDM5, both of which were discovered by the
laboratory.
The studies on MUC1 have led to investigations into changes in glycosylation
that occur in breast cancer. This field has greatly influenced the immunology
studies and we are actively exploring the binding of tumour-associated glycoforms of MUC1 with lectin-like receptors of the immune system. We are also studying of auto-antibodies reactive with MUC1 tumour-associated glycopeptides in breast cancer patients, and their correlation with prognosis. The involvement of aberrant O-linked glycosylation in the development and progression of breast cancers is also a major focus.
JARID1B/KDM5 is a histone demethylase that is expressed in breast cancers and the developing mammary gland while expression in other normal tissues is limited to the testis. These studies centre around its function in normal mammary gland development and in breast cancer and has led to an interest in epigenetic of breast cancer.
Glycosylation
The change to malignancy is associated with changes in the glycans attached to glycolipids and glycoproteins and evidence is now accumulating that this can have a fundamental effect on the tumour cell. The particular form glycosylation of proteins that we are studying is O-linked glycosylation, where glycans are O-linked to serine and/or threonine and the sugars are added individually and sequentially. This type of glycosylation is found on mucin-type molecules or glycoproteins containing mucin-like domains. Our previous work has demonstrated that changes in the expression of glycosyltransferases in breast carcinomas compared to normal breast epithelial can explain, at least in part, the changes in O-linked glycans observed in breast cancers. In particular, two sialyltransferases are upregulated at the RNA level.
We have particularly been studying the membrane mucin known as MUC1, which is
upregulated and aberrantly expressed in breast and other carcinomas. The staining of an antibody that specifically recognises MUC1 carrying tumour-associated glycans shows that greater than 90% of breast carcinomas aberrantly glycosylate their O-linked glycans, suggesting that this may elicit some benefit to the tumour.
Projects
We are looking at how particular tumour-associated glycoforms of MUC1 interact with immune cells to stimulate an immune response and suppress an immune response.
We also plan to map histone marks in progenitor and differentiated cells of the
mammary gland and integrate these with gene expression.
Mr Michael Douek's translational research program evaluates novel devices and imaging modalities to improve breast surgery for cancer. This includes the clinical applications of nanotechnology for sentinel node biopsy, intraoperative radiotherapy and novel devises for breast reconstruction.
Mr Douek is the Chief Investigator of the SentiMAG trial of sentinel node biopsy and of the POBRAD trial (prospective trial of acellular dermal matrix for implant breast reconstruction). He is also Principal Investigator for the international randomised controlled trial of intra-operative radiotherapy (TARGIT trial), at Guys Hospital.
She serves on the Cancer Research UK Biomarkers in Clinical Trials Committee, the National Cancer Intelligence Network (NCIN) Breast Reference Group, the NHS Breast Screening Programme Pathology Co-ordinating Committee, the Sloane Project (UK National DCIS audit) Steering Group and Chairs the NHS Breast Screening Programme Pathology Research Committee. She is Associate Editor for Breast for Histopathology.
Her research interests are focused on breast cancer diagnosis and prediction of prognosis, with a particular interest in precursor lesions, with emphasis on correlation of the morphology, protein expression and molecular and genetic features. She leads the KCL Breakthrough Breast Cancer Research Unit’s investigation into the molecular pathology and biology of the precursors of invasive breast carcinoma, particularly of basal-like type.
She has published over 180 peer-reviewed articles, over 50 invited reviews, and more than 40 chapters on breast diseases in medical textbooks.
