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Title: Targeting the VLA-4/VCAM-1 interaction for the diagnosis and prevention of brain metastases
Author: Cheng, Vinton
ISNI:       0000 0004 7971 6465
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2019
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Background: Brain metastasis is a major cause of cancer patient morbidity and mortality. The late stage of diagnosis and the difficulty in defining the tumour boundary both contribute to the lethality of brain metastases. Cell adhesion molecules (CAMs), such as very late antigen-4 (VLA-4) and its ligand vascular cell adhesion molecule-1 (VCAM-1), have been implicated in the metastatic process. By targeting the VLA-4/VCAM-1 interaction, I applied different methods to improve the diagnosis of brain metastases and to prevent their formation. Aims: (i) To determine if VCAM-1 targeted MRI is able to detect brain micrometastases from different tumour types in mouse models; (ii) to determine if VCAM-1 targeted MRI is able to detect the brain metastasis invasive margin in rat models; and (iii) to determine if tumour cell VLA-4 knockdown inhibits metastatic spread of cancer to the brain in mouse models. Findings: VCAM-MPIO MRI could detect brain metastases of different tumour types before gadolinium enhanced T1-weighted MRI. Furthermore, the imaging contrast improved delineation of the invasive margin of brain macrometastases on T2*-weighted MRI, when used in conjunction with conventional techniques. Whilst knockdown of VLA-4 does not entirely prevent brain metastasis formation, the trend to benefit suggests testing in combination with knockdown of other CAMs may yield a significant reduction in metastatic potential. Discussion: I present a multi-faceted approach, exploiting the roles of VLA-4 and VCAM-1 in brain metastatic formation and progression, for improved diagnosis of brain micro/macrometastases and possible inhibition of metastatic seeding in the brain. Future studies will focus on improving the preventative capacity of anti-CAM therapy and the clinical translation of VCAM-MPIO MRI to human applications.
Supervisor: Sibson, Nicola ; Middleton, Mark Sponsor: CRUK/MRC Oxford Institute for Radiation Oncology
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Neuroimaging ; Oncology, Experimental ; Cancer invasiveness