Novel targeted contrast agent for early detection of brain metastasis: from animal to patient stage 2

Metastasis is the spread of cancer from the initial site, e.g. breast or lung, to a secondary or different part of the body. Metastasis to the brain is one of the most feared complications of cancers such as breast and lung, as it is rarely detected at a stage when it can be treated, and life expectancy once diagnosed is generally only a few months. Magnetic resonance imaging (MRI) is widely used for diagnosing brain tumours (cancer). These MRI methods use so-called contrast agents, which can be thought of as dyes that alter the intensity or brightness of the images in the areas where they are present. Until now the contrast agents used in cancer diagnosis have needed major damage to the brain blood vessels to occur before their accumulation within the tumour can be seen in the images. As a result, these methods are only able to detect tumours that are well established, and 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 agent that does not need to accumulate within the tumour via leaky blood vessels. Instead these contrast agents will bind to the surface of the blood vessels that is directly in contact with the blood when certain molecules are present on the vessels. We have found that the levels of a particular molecule called VCAM-1 are increased on blood vessels that are closely associated with early metastases in the brain. This VCAM-1 expression occurs long before damage to the blood vessels. Using a contrast agent that will bind to VCAM-1, we believe that we have found a way to detect early brain metastases when they cannot otherwise be seen. Under our current MRC DPFS award we have converted our VCAM-1-targeted contrast agent into a form that can be used in humans. We have verified binding of this humanised agent to the target human molecule and will soon start in-depth testing of the agent for any damaging or toxic effects in the body that would prevent its use in man. Under the current application, therefore, we propose to manufacture the humanised contrast agent to the levels required for human use and to obtain the ethical and regulatory approvals required for human trials. When these approvals are in place, we will undertake a Phase I/IIa clinical trial in cancer patients with known brain metastases. The primary aim of this study will be to assess safety, but it will be designed such that we can also obtain preliminary information as to how effective the contrast agent is in detecting metastases in the brain. 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 devastating disease are treated and managed.