Our goals are to identify the role of the inflammatory and metabolic microenvironment in brain metastasis, and to develop imaging biomarkers for tumour detection and monitoring.
Metastasis (secondary cancer) to the brain is a significant clinical problem and prognosis is extremely poor. The incidence of brain metastasis is increasing as patients survive longer, and even radiosurgery/radiotherapy has limited impact on prognosis.
We have identified three critical hurdles to effective treatment of brain metastases: (1) late stage of diagnosis; (2) poor access to the brain (bioavailability) of therapies that are successful in peripheral tumours; and (3) impact of microenvironmental factors on the effectiveness of treatment. By improving our understanding of the microenvironment of brain metastases, we believe that we will not only identify new therapeutic targets, but also drive the development of diagnostic imaging tools for use in patients.
Earlier detection of brain metastases is likely to yield substantial gains both for current therapies and the development of new metastasis inhibiting agents. To this end, we have demonstrated that it is possible to detect brain metastases at a much earlier stage than current clinical methods allow, through the use of new molecularly-targeted imaging agents (Fig. 1).
In collaboration with others in the University, we developed and patented biodegradable microparticles of iron oxide (MPIO) as a platform for translating this technology to man. Together, this work has formed the basis of two successful applications to the MRC Developmental Pathways Funding Scheme to progress this agent to a Phase I/IIa clinical trial.
With regards to bioavailability, a significant hurdle is the presence of the blood-brain barrier (BBB). We have recently shown that it is possible to make the BBB selectively leaky at sites of brain metastasis, and that this approach enables metastasis-targeted delivery of both diagnostic agents and relevant therapies (Fig. 2).
The above on-going studies feed into our overall research programme, in which our primary aims are to (1) determine the role of inflammatory processes in brain metastasis development and response to radiotherapy, and (2) develop novel approaches to imaging the tumour microenvironment for early diagnosis and treatment monitoring.
Figure: 1(A) Confocal microscopy images showing co-localisation of the cellular adhesion molecule VCAM-1 (red) on vessels associated with a micrometastasis (green) in mouse brain. Cell nuclei stained blue.
Figure: 1(B) MRI detection of VCAM-1 expression on brain blood vessels using VCAM-1-targeted MPIO in a mouse model of brain metastasis; 3D reconstruction showing spatial distribution of VCAM-MPIO binding (in red) indicating sites of metastases throughout the brain.
Figure: 2 SPECT image showing accumulation of radiolabelled Trastuzumab at the site of a micrometastatic colony in mouse brain following selective permeabilisation of the metastasis-associated vasculature.
Nicola Sibson is Professor of Imaging Neuroscience and CRUK Senior Group Leader, at the CRUK/MRC Oxford Institute for Radiation Oncology. Following her PhD, Nicola spent 4 years at Yale University before joining the MRC Biochemical and Clinical Magnetic Resonance Unit in Oxford. She then moved to the Department of Physiology, Anatomy and Genetics as a University Research Lecturer and joined the Oxford Institute in 2007. She has given numerous plenary lectures at national and international meetings, including the prestigious British Neuropathological Society Lecture at the Neuro-Oncology Society Annual Conference. She serves on funding panels and advisory boards and was recently made a Special Supernumerary Fellow of University College Oxford.
Larkin, J. R., Dickens, A.M., Claridge, T.D., Bristow, C., Andreou, K., Anthony, D.C. and Sibson, N.R. (2016). Early Diagnosis of Brain Metastases Using a Biofluids-Metabolomics Approach in Mice. Theranostics, 6(12), 2162. doi:10.7150/thno.16538.
Soto, M.S., O’Brien, E.R., Andreou, K., Scrace, S.F., Zakaria, R., Jenkinson, M.D., O’Neill, E. and Sibson, N.R. (2016). Disruption of tumour-host communication by downregulation of LFA-1 reduces COX-2 and e-NOS expression and inhibits brain metastasis growth. Oncotarget. doi: 10.18632/oncotarget.1073.
Ray, K.J., Larkin, J.R., Tee, Y.K., Khrapitchev, A.A., Karunanithy, G., Barber, M., Baldwin, A.J., Chappell, M.A. and Sibson, N.R. (2016). Determination of an optimally sensitive and specific chemical exchange saturation transfer MRI quantification metric in relevant biological phantoms. NMR in Biomedicine, 29(11), 1624-1633. doi:10.1002/nbm.3614.
Melemenidis, S., Jefferson, A., Ruparelia, N., Akhtar, A. M., Xie, J., Allen, D., Hamilton, A., Larkin, J.R., Perez-Balderas, F., Smart, S.C., Muschel, R.J., Chen, X., Sibson, N.R., Choudhury, R. P. (2015). Molecular magnetic resonance imaging of angiogenesis in vivo using polyvalent cyclic RGD-iron oxide microparticle conjugates.. Theranostics, 5(5), 515-529. doi:10.7150/thno.10319.
Sarmiento Soto M., Serres S., Anthony D.C., Sibson N.R. (2014) Functional role of endothelial adhesion molecules in the early stages of brain metastasis. Neuro-Oncology 16:540-51.
Connell J.J., Chatain G., Cornelissen B., Vallis K., Hamilton A., Seymour L., Anthony D.C. Sibson N.R. (2013) Selective permeabilisation of the blood-brain barrier at sites of metastasis. Journal of the National Cancer Institute :105:1634-43.
Serres S., Sarmiento Soto M., Hamilton A., McAteer M.A., Carbonell W.S., Robson M.D., Ansorge O., Khrapitchev A., Bristow C., Balathasan L., Weissensteiner T., Anthony D.C., Choudhury R.P., Muschel R.J., Sibson N.R. (2012) Proceedings of the National Academy of Science USA. 109:6674-9.