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: (i) late stage of diagnosis; (ii) poor brain bioavailability of systemically successful therapeutics; and (iii) impact of microenvironmental factors on treatment efficacy. 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 clinically translatable diagnostic imaging tools.
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 (e.g. 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.
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 selectively permeabilise the BBB at sites of brain metastasis, and that this approach enables metastasis-targeted delivery of therapeutics (e.g. Fig. 2) resulting in a significant reduction in tumour volume. We are currently progressing this work towards clinical trial.
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.
Finally, it is clear that the brain microenvironment is significantly different to other tissues, and we have identified key responses within the inflammatory cell populations that both promote and inhibit tumour growth. Harnessing the anti-tumour responses specifically may provide a potent new therapeutic strategy for brain metastasis.
To achieve our goals, we use a combination of in vivo models, macroscopic and microscopic imaging, immunohistochemistry and molecular biology methods.
We currently have four primary areas of research that are at different stages of progression to clinical translation:
- Early detection of brain metastasis by VCAM-1 targeted MRI. This work has been funded through two consecutive translational MRC DPFS awards and we are currently seeking further funding to undertake the final stages of scale up, toxicology and phase I/IIa clinical trial. This work has two associated patents.
- Permeabilisation of brain metastases with a TNF mutein. This work has also been funded under two consecutive translational MRC DPFS awards and at the end of the current award we will be ready to undertake a phase I/IIa clinical trial. This work has two associated patents.
- Imaging glioblastoma pH using CEST-MRI (IMAGO). This is a clinical trial that arose directly from a DPhil project, joint with Prof. Michael Chappell’s group, in which we were developing CEST MRI for the assessment of tumour pH. The clinical trial, run by Dr Simon Lord (Oncology), is now complete and data analysis is underway.
- Oxomics. We are currently seeking funding for a spin-out company based on our metabolomics work, in which we have recently shown that we can identify patients who present with non-specific signs as having cancer or no cancer from simple NMR analysis of blood or urine samples. This work is based on a long-standing collaboration between our group, Prof. Daniel Anthony’s group (Pharmacology) and Prof. Tim Claridge’s group (Chemistry Research Laboratory), and has given rise to 3 patents to date.
In addition to the above, all of our basic research is designed with the overall, long-term goal of clinical translation.
Currently, our main focus lies in the TNF-mediated BBB permeabilization project, which is driven ‘on the ground’ by Dr Vanessa Johanssen (PDRA) and Claire Bristow (RA), with Project Management from Dr Sandra Campbell. Together, we are a tight-knit team and work closely together to ensure that we achieve our aims. These DPFS projects are run to a very tight timeline, with regular reporting to the MRC, and as such require considerable focus and commitment to meeting our deadlines. We also have a joint DPhil student with the Ludwig Institute for Cancer Research, Emily Steffke, who is funded on an Oxford-NIH studentship and due to return to the US shortly. Her project is focussed on the development of vaccine-based approaches to glioblastoma therapy.
- Cheng V.W.T., de Pennington N., Zakaria R., Larkin J.R., Serres S., Sarkar M., Kirkman M.A., Bristow C., Croal P., Plaha P., Campo L., Chappell M.A., Lord S., Jenkinson M.D., Middleton M.R., Sibson N.R. (2022) VCAM-1-targeted magnetic resonance imaging improves detection of the tumor-brain interface. Clin. Cancer Res. 28:2385-2396.
- Economopoulos V., Pannell M., Johanssen V.A., Scott H., Andreou K.E., Larkin J.R., Sibson N.R. (2022) Inhibition of anti-inflammatory macrophage phenotype reduces tumour growth in mouse models of brain metastasis. Front. Oncol. 12:850656.
- Larkin J.R., Anthony S., Johanssen V.A., Yeo T., Sealey M., Yates A.G., Smith C.F., Claridge T.D.W., Nicholson B.D., Moreland J.A., Gleeson F., Sibson N.R., Anthony D.C., Probert F. (2022) Metabolomic biomarkers in blood samples identify cancers in a mixed population of patients with nonspecific symptoms. Clin. Cancer Res. 28:1651-1661.
- Munoz Pinto M.F., Campbell S.J., Simoglou Karali C., Johanssen V.A., Bristow C., Cheng V.W.T., Zarghami N., Larkin J.R., Pannell M., Hearn A., Chui C., Brinquis Nunez B., Bokma E., Holgate R., Anthony D.C., Sibson N.R. (2021) Selective blood-brain barrier permeabilisation of brain metastases by a type-1 receptor selective tumour necrosis factor mutein. Neuro-Oncol. 24(1):52-63.
- Sarmiento Soto M., Larkin J.R., Martin C., Khrapitchev A.A., Maczka M., Economopoulos V., Scott H., Escartin C., Bonvento G., Serres S., Sibson N.R. (2020) STAT3-mediated astrocyte reactivity associated with brain metastasis contributes to neurovascular dysfunction. Cancer Res. 80:5642-5655.
- Ray K.J., Simard M.A., Larkin J.R., Coates J.T., Kinchesh P., Smart S., Higgins G.S., Chappell M.A., Sibson N.R. (2019) Tumour pH and protein concentration contribute to the signal of amide proton transfer magnetic resonance imaging. Cancer Res. 79:1343-1352.
- Cheng V.W.T., Sarmiento Soto M., Khrapitchev A.A., Perez-Balderas F., Zakaria R., Jenkinson M.D., Middleton M.R., Sibson N.R. (2019) VCAM-1 targeted magnetic resonance imaging enables detection of brain micrometastases from different primary tumours. Clin. Cancer Res. 25:533-543.
- Perez-Balderas F., van Kasteren S.I., Aljabali A.A.A., Wals K., Serres S., Jefferson A., Sarmiento Soto M., Khrapitchev A.A., Larkin J.R., Bristow C., Lee S.S., Bort G., De Simone F., Campbell S.J., Choudhury R.P., Anthony D.C.§, Sibson N.R.§, Davis B.G.§ (2017) Covalent assembly of nanoparticles as a peptidase-degradable platform for molecular MRI. Nat. Comm. 8:14254.
- Sarmiento Soto M., O’Brien E.R., Andreou K., Scrace S.F., Zakaria R., Jenkinson M.D., O’Neill E., 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 7:52375-52391.
- 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. J. Natl. Cancer Inst. 105:1634-1643.