Novel targeted contrast agent for early detection of brain metastasis: from animal to patient

Metastasis is the spread of cancer from the initial site, e.g. breast or lung, to another part of the body. Metastasis to the brain is one of the most feared complications of cancers such as breast and lung, as they cannot be detected at a stage when they can be treated and life expectancy once diagnosed is generally only a few months. Magnetic resonance imaging (MRI) is widely used for diagnosing brain cancer, but the techniques are only sensitive to tumours that are large and well advanced. These MRI methods use so-called contrast agents, which can be thought of as dyes that alter the colour or intensity of the images in the areas where they are present. Until now the contrast agents used in cancer diagnosis have been passive in that they require major damage to the brain blood vessels to allow their passive accumulation within the tumour. As a result, treatments that might have been successful at earlier stages do not work, because the disease is too far advanced. To overcome this problem, we have been developing a new type of MRI contrast agents that will actively bind to specific molecules associated with disease, and identify areas where levels of these molecules are increased. We have found that the levels of certain molecules on the blood vessels in the brain are increased early in the development of brain disease. In particular, we have identified specific molecules that are increased in the early stages of brain metastasis. By designing contrast agents that will bind to these specific molecules, we believe that we have found a way of detecting early brain metastasis when it cannot otherwise be seen. We have already shown that our targeted contrast agent works in mouse models of brain metastasis. The first aim of this project, therefore, is to take our agent and convert it to a form that will work in humans. We will then test this humanised form of the agent both for detection of the target human molecule and for any potentially harmful or toxic effects. When we have completed the work in this proposal, the humanised contrast agent will be taken forward into a clinical trial. We believe that our approach will greatly improve our ability to diagnose brain metastases in the early stages and, as a result, change the way in which patients with this currently incurable disease are treated and managed.

Metastatic spread of a primary tumour to the brain remains one of the greatest hurdles in cancer therapy, and prognosis is poor. Magnetic resonance imaging (MRI) is commonly used for the diagnosis of brain cancer, but current, gadolinium-enhanced techniques are sensitive only to larger, late stage tumours ( 5mm), when therapeutic potential is limited. Our approach, capable of detecting 200um tumours, will enable much earlier detection of brain metastases. We have developed targeted MRI contrast agents, which detect specific molecules expressed early in disease. We have shown that our new patent-protected contrast agent, targeting the endovascular adhesion molecule VCAM-1, enables early detection of metastases in mouse brain when they are undetectable by existing clinically-used methods. Importantly, we have also demonstrated expression of VCAM-1 in human post-mortem brain tissue containing micrometastases. We believe that early diagnosis of brain metastases using our contrast agent will increase therapeutic options and change clinical management of a substantial number of cancer patients. Our aim here is to fully humanise the targeting anti-VCAM-1 antibody and to take the humanised contrast agent through preclinical and toxicological testing, prior to clinical trials. Our approach has already generated considerable interest amongst both Oncologists and Imaging Companies.