Title: MRI and MRS of Cancer
Funder: Cancer Research UK

Abstract: In our proposed program of translational research for the next quinquennium we intend to pursue and extend our existing projects and to design new proposals that will incorporate full use of the facilities offered at CRI such as genomics, proteomics, histopathology, microscopy, PET, SPECT etc. Our projects will fall mainly under the headings of metabolomics, preclinical MRI & MRS and clinical MRI & MRS. _x000D_ _x000D_ Metabolomics Over the last few years my group has pioneered a number of uses of ex vivo NMR to analyse metabolomics in cancer. Metabolomics can identify molecular targets of disease prevention and treatment, and also improve our understanding of the underlying disease processes and tumorigenesis. We are already collaborating extensively with CRI groups in metabolomic studies on senescence, various mouse tumour models and biopsies from patients. Recently (in collaboration with the Narita group and Bioinformatics) we devised a way to perform metabolite correlation analysis on tumour cells which we plan to apply to metabolic pathway analysis using the INGENUITY platform. We also plan to develop methods to integrate these metabolomics data with other '-omics data so as to utilise systems biology in cancer. This method will be applied to our other projects. _x000D_ _x000D_ Preclinical MRI and MRS of cancer in mouse models. In addition to our established multinuclear MRS and MRI techniques (e.g. 1H, 31P, 19F and 13C MRS, DCE-MRI, BOLD and DWI) we will develop new methods, primarily directed at the extracellular matrix and assessment of pH, pO2 and hypoxia. These will include CEST (chemical exchange saturation transfer) quantitative magnetisation transfer and methods to quantify lipid and lactate as markers for necrotic or hypoxic tissue, and the development of a TET-controlled endogenous protein that cancer cells can be engineered to express. These new techniques will be applied both in-house and for internal and external collaborations, and where practicable, will be translated into the clinic. For example, we are beginning a project with Duncan Jodrell in which preclinical 19F MRS studies of capecitabine metabolism will underpin clinical studies. These collaborations will benefit from the synergy between our advanced MR methods and our CRI collaborators' genetically modified mouse tumour models, especially in pancreas and gut. Additionally we will continue to use xenograft models, some with engineered cell line variants, of the tumours of major interest within the CRI, and will set up an MR-compatible window chamber tumour system._x000D_ _x000D_ Clinical projects Our aim here is to translate promising preclinical methods into the clinic. We will explore the biology of the tumour microenvironment using magnetization transfer MRI and MRS (and CEST if this proves feasible). We will develop and apply image processing techniques such as texture analysis to enhance early detection and prediction of metastatic spread of disease. The methods developed will be applied in multiple cancer subtypes, in collaboration with our wide circle of clinical colleagues. _x000D_ _x000D_ We have initiated a collaboration with Duncan Jodrell that will implement 19F MRS for non-invasive monitoring of anticancer drugs. We will also support the imaging aspects of the extensive early-phase clinical trial programme that Duncan has under development at CRI. This will capitalize on the clinical resources of the West Anglia Cancer Research Network, one of the most active in the country, covering a population of 1.65 million._x000D_ _x000D_ Finally, we will continue our work validating MR biomarkers such as choline, lactate, lipids, diffusion and contrast enhancement. Validated biomarkers could be used not only as research tools, but also as surrogate endpoints in clinical trials of new treatments (e.g. our in on-going collaboration with Merck & Co.) and ultimately in the clinic for routine diagnosis, prognosis and treatment monitoring. _x000D_


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;4.4 POPULATION SCREENING
Health categories: CANCER AND NEOPLASMS