Tumour Biology and Immunology

Group
  • Unit(s) of assessment: Allied Health Professions, Dentistry, Nursing and Pharmacy
  • School: School of Science and Technology

Overview

The group conducts fundamental and translational research into a range of cancers, including breast, colorectal, pancreatic, liver, prostate, skin (malignant melanoma), brain (glioblastoma multiforme) and ovarian, as well as leukaemia. The research focuses on the unmet clinical needs via pre-clinical and clinical research into the identification of biomarkers for diagnostic, disease prediction and therapeutic response. The group is also developing peptide and DNA-based vaccines and cell-based immunotherapeutic strategies for the treatment of aggressive disease. These studies are interrogating important molecular pathways and the key events associated with malignancy using state-of-the-art analytical platforms such as cell cytometry, mass spectrometry and gene expression arrays, and are supported by advanced bioinformatics and computational capabilities.

The importance of tumour suppressor genes such as p53 and PML and newly identified cancer antigens such as HAGE and T21 are being investigated, not only for their respective roles in the cancer process, but also as targets for therapy. Cancer stem cell (CSC) and Epithelial to Mesenchymal Transition (EMT) research addresses the need to better understand the biology of metastatic disease (which is responsible for ~90% cancer-related deaths) and the role of these cells and processes in cancer progression and drug-resistance. Studies are also interrogating Imatinib resistance in patients with chronic myeloid leukaemia (CML) and resistance to interferon treatment in melanoma.

Recent interests include the epigenetic nature of oncogenic transformation, cancer growth and metastasis, and the links between the nuclear response and the cellular response to stresses involving metabolic and epigenetic regulators. Epigenomic and transcriptomic high-throughput analyses are providing insight into the interplay between genetic and post-genetic mechanisms underlying oncogenesis. The role of epigenetic modifiers and non-coding RNAs (microRNAs and long non-coding RNAs) in regulating disease-associated gene networks are providing insights into key molecular pathways such as tumour-stromal interactions, chronic inflammation, tumour aggressiveness and chemoresistance.

The cancer immunotherapy programme incorporates a number of strategic aims. New approaches targeting histone modifiers, microRNAs and lncRNAs are being evaluated in pre-clinical animal models, either as stand-alone or combinatorial therapies. Tumour antigens and peptide epitopes that can be recognised by MHC-restricted CD4+ and CD8+ T cells, and form the basis of new therapeutic cancer vaccines are being evaluated as potential target antigens. In collaboration with a number of international partners, we are developing new antibody-based therapeutics, the nature of which is being informed by our ‘omics’ and CSC / EMT programmes, and strategies for targeting the large proportion of tumours that express a unique membrane form of the 70 kDa heat shock (stress) protein, Hsp70. Other studies are developing natural killer (NK) cell based therapeutics (in collaboration with commercial partners) and determining whether the induction of tumour cell senescence can induce the sensitivity of cancer cells / tumours to innate immunity. The capacity of the latest generation of ‘checkpoint inhibitors’ to further enhance the efficacy of these immunotherapeutic approaches is also being examined. Finally, studies are identifying specific gene signatures and molecular pathways within the immunological tumour microenvironment that reflect immune system activation, and which can help to predict treatment response and the risk of relapse in patients with cancer.

Projects

Bioinformatics analysis of Prostate cancer immunophenotyping

Analysis using our Flow Cytometry facility is currently conducted using a 2D gating system on the cell population. Currently gating analysis is driven by the pre-conceived ideas of the investigator and the findings generated are entirely dependent on the placement of these gates and the expectations of the person undertaking the analysis. Thus, this study aims to establish a new strategy that can alleviate user subjectivity of the gating technique and to identify more accurate features from immune profiles to help determine the underlying immunity cause of prostate cancer.

Bioinformatics Analysis of flow cytometry profiles in patients with leukaemia

This project is the collaboration work with Dr. Ricardo Morilla (Clinical Scientist, Head of Immunophenotyping, the Royal Marsden Hospital, Sutton), to identify patient subsets from immune profiles that can delineate crucial stages of leukaemia progression and can be used in the clinical environment to improve patient care. Artificial Neural Network data mining has been used to perform in depth interrogation on the blood and bone marrow flow cytometry data provided by Dr. Morilla. This project has started recently and results from the project are expected during the next 12 month period.

Gene Expression Profiling

This project is concerned with the development of gene micro-arrays for identifying genes/proteins and immune phenotypes that are associated with the severity and progression of prostate cancer by:

  • Establishing mRNA expression arrays for the identification of new genes/antigens by Bioinformatics mining using laser capture micro-dissected prostate cancer cells from benign tissue and tissue with pathologist-confirmed disease
  • Establishing gene expression arrays for key immune profile markers using lymphocyte sub-populations purified by cell sorting (by Fluorescence Activated Cell Sorting) from the blood of patients with prostate cancer. Initial studies will focus on immunoregulatory (suppressor) T cells.

This project will generate an internationally recognised resource and provide a platform on which to discover new biomarkers for the diagnosis and prognosis of prostate cancer.

Systems Biology in Breast Cancer

This study builds on the previous work in which new systems biology approaches have been developed for the analysis of gene expression array data to address key issues related to patient clinical management, for example, to establish a greater understanding of the Estrogen Receptor system. This project aims to use customised artificial neural network algorithms developed at NTU to enhance previous research conducted in modelling network pathways. These will be applied in the analysis of various sources of data (for e.g. transcriptomic arrays) in breast cancer. This will identify additional detailed models and possibly co-therapies and new biomarkers for breast cancer. Preliminary results have helped us identify core proliferation, cell cycle and DNA repair biomarkers involved in Breast cancer. Furthermore a systems biology approach based on ANN will be implemented to enhance our knowledge of the pathways involved in causing resistance to the drug tamoxifen in approximately one-fourth of breast cancer patients.

Immune profiling patients with prostate cancer

We have established a study that will determine markers of immunity correlating with clinical diagnosis in prostate cancer patients.This clinical trial commenced in 2012 with the aim of comparing the diagnostic accuracy of two biopsy techniques in 200 patients. The Clinical Lead is Masood Khan (Head of Urology, Leicester and Visiting Professor at JvGCRC). We are undertaking the analysis of patient blood serum, urine and blood leukocytes and we have identified new protein and immune cell markers that appear to be indicative of the presence of disease. The trial is designed to enhance the accuracy of patient diagnosis of "tiger versus pussycat / aggressive versus indolent" disease status. A main component of the study formed the basis for a successful application for iNET funding ~£226,000, which specifically addresses the role of urine biomarkers in diagnosis.

Related staff

  • Professor Graham Ball - cancer biomarkers, gene expression, proteomics, bioinformatics, breast cancer
  • Dr David Boocock - proteomics, biomarkers, diagnosis, tumour prognosis
  • Dr Amanda Coutts - Cancer, p53 and its co-factor JMY, autophagy and cell survival
  • Dr Maria Hatziapostolou - cancer growth and aggressiveness, epigenetic regulation, genome-wide analyses, pancreatic and liver cancer
  • Dr Stephanie McArdle - Cancer immunology, immunotherapy, cancer vaccines,
  • Dr Cristina Montiel-Duarte - CML - chronic myeloid leukaemia, BCR-ABL, drug resistance
  • Professor Graham Pockley - Membrane Hsp70, immunobiology, heat shock proteins, immunological biomarkers, innate immunity, adaptive immunity, flow cytometry
  • Professor Robert C Rees - Cancer immunology, immunotherapy, cancer vaccines, proteomics, biomarkers, diagnosis, tumour prognosis
  • Dr Christos Polytarchou - inflammatory bowel diseases, gastrointestinal cancer, micro RNA and non-coding RNAs, epigenetic regulation.
  • Dr Tarik Regad - HAGE, cancer aggression, molecular pathology, malignant melanoma, prostate cancer, PML, tumour suppressor gene, cancer stem cells

Publications

Selected publications are listed on the staff members' profile pages

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