Research

Tumour cell biology

Normal cells adapt to hypoxia by the HIF-1 pathway, which is upregulated in many cancers and accelerates their growth; it also upregulates their glycolytic pathway. Monika Golinska's PhD project (in collaboration with Adrian Harris, University of Oxford), is on Hepa c4 tumours, which cannot activate HIF-1 or upregulate glycolytic enzyme expression but still perform glycolysis normally. Interestingly, Monika has found that they upregulate glycolysis allosterically by maintaining low ATP and high AMP, which doubles the activity of phosphofructokinase-1, the main regulatory enzyme of glycolysis. The high AMP in c4 tumours also upregulates AMP-dependent protein kinase, which tends to slow their growth. These results suggest a mechanism whereby tumours might resist the anti-HIF drugs that are under development, and that monitoring tumour glycolysis by FDG-PET would not necessarily indicate whether they are working in a patient.

Also in collaboration with Adrian Harris, Shen-Han Lee, a PhD student, is studying the role of the enzyme carbonic anhydrase IX (which converts CO2 to bicarbonate and which is overexpressed in many cancers) on tumour extracellular pH (pHe). Using ISUCA, a pH sensitive MRS probe, Shen-Han has shown that tumours that overexpress carbonic anhydrase IX tend to have lower pHe. He is now looking at the role of this mechanism in tumour growth and metastasis.

Metabolomics

Madhu Basetti leads several metabolomics projects, including a study of cellular senescence in collaboration with the Narita laboratory. Senescence is a fail-safe mechanism to prevent malignant transformation of cells when their genome is under stress. In this project Madhu (in collaboration with the Tavaré laboratory) has implemented a novel method of metabolite-metabolite correlation analysis, which has demonstrated numerous unexpected metabolic interactions, many of which are altered by the induction of senescence. Tonci Sustic, a new joint PhD student with Masashi Narita, will be working on the metabolomics of senescence and autophagy.

Another metabolomics project is being performed by Sara Dietz, a joint PhD student with Colin Watts (Department of Neurosurgery), on the characterisation of the metabolome in stem-like cells derived from human glioblastoma multiforme tissue, and in cell lines produced by inducing differentiation in these cells. Sara has observed marked metabolic differences between the cell types.

Preclinical MRI and MRS

Preclinical MRI and MRS studies are led by Dominick McIntyre, together with Davina Honess. Leanne Bell's PhD project is on the Tuveson laboratory's KPC pancreatic tumour model that, like human pancreatic tumours, responds poorly to gemcitabine, the current standard of care for this cancer. In previous studies with the Tuveson laboratory (Olive et al., Science 2009; 324: 1457) we demonstrated that the vascular insufficiency in KPC tumours, which is probably due to their dense collagenous stroma, contributes to their chemoresistance. Leanne has continued DCEMRI studies of the vasculature and developed magnetisation transfer MRI methods to monitor the tumour matrix in the KPC mouse model and ectopic KPC allografts. She will now be collaborating with the Tuveson laboratory on studies using novel anticancer drugs designed to break down the collagenous matrix of KPC tumours and enhance the action of gemcitabine, using magnetisation transfer as a biomarker of matrix breakdown.

Nicola Ainsworth, a clinical research fellow (jointly supervised by Jonathan Gillard, Department of Radiology, and in a collaboration with Susan Harden, Department of Oncology), is studying cerebral metastasis of small cell lung cancer (SCLC). About half of patients with SCLC develop cerebral metastases, but since we cannot predict which half, the current practice is to give all of them prophylactic cranial irradiation, a therapy with significant long-term side effects. Nicola's project is aimed at developing MR methods for detecting these metastases much earlier, so that patients who would not benefit from prophylactic cerebral irradiation can be spared this therapy. Nicola has developed a mouse model of brain metastasis and she is developing various MRI methods, including magnetisation transfer, which could be used in patients. She is also recruiting SCLC patients, nine so far, into a study (CLUB-01) in which they are imaged before and after prophylactic cranial radiotherapy.

We are continuing our joint programme with Martin Leach, Ian Judson and Paul Workman (Institute of Cancer Research, Sutton) on monitoring the actions of novel anticancer drugs by MRS and MRI, in order to develop non-invasive biomarkers for use in drug trials or in the clinic.

Figure 1
MRI of a patient's brain showing brain metastases from non small cell lung cancer. The red arrows indicate the metastases. (A) T2 weighted scan showing extensive oedema. (B) Fractional anisotropy colour map showing location and direction of white matter tracts, which are disrupted by the tumour. Red: right to left; green: front to back; blue: head to foot.

Clinical MRI and MRS

Mary McLean leads our work on tumours in patients. We are collaborating with James Brenton (CRI) and Evis Sala (Department of Radiology) in an MRI and MRS study (OVO3) on the response to chemotherapy of cancer of the ovary. Three papers have been published.

We are continuing our participation in an NCI-funded international collaboration, which has developed a method for individualising therapy for patients with non-Hodgkin's lymphomas by using MRS to predict response; 16 studies have been performed.

Another collaboration with Evis Sala, Vincent Gnanapragasam (Department of Surgery) and David Neal (CRI) is concerned with the use of DWI, DCE-MRI and MRS for prediction and early detection of prostate cancer response to androgen deprivation in advanced prostate cancer. We have so far performed 47 examinations on 25 patients. One paper is in press and another in preparation.

In a collaborative study with the Jodrell laboratory we are developing methods for quantification of the oral anticancer drug capecitabine and its metabolites in breast tumours and in the liver. Five patients have so far been studied and both capecitabine and its metabolite fluoro-beta-alanine have been detected; preclinical studies are also planned.

Sidhartha Nagala is taking a PhD under the supervision of Jonathan Gillard (Department of Radiology) on the use of MRS and DWI for the diagnosis of cancer in follicular thyroid nodules and parotid lumps. Thirty eight examinations have been performed so far. Tumour biopsies from these examinations will be studied by HRMAS 1H MRS to correlate metabolomics data with the clinical findings. Accurate preoperative diagnosis, which is difficult for these lesions, will enhance surgical planning as well as reducing unnecessary operations.