Angiogenesis imaging in the post-genomic era.

With the US Food and Drug Administration’s (FDA) approval of Avastin (bevacizumab; Genentech, Inc., San Francisco, CA) as a first-line treatment for patients with metastatic colorectal cancer, the field of angiogenesis received a great and much needed boost. Although a major landmark has been achieved with this first FDA approval of an angiogenesis inhibitor for cancer treatment, much work still needs to be done before angiogenesis therapies can fulfil the expectations of many investigators in the field. The question that we are exploring in this special issue of the British Journal of Radiology is what roles imaging can play in facilitating the translation of the many advances we have made on the bench to the bedside in the field of angiogenesis. In an ideal scenario, an imaging biomarker should be able to depict pathological angiogenesis, help to select patients for appropriate therapeutic regimens including the most appropriate combination of angiogenic and other therapeutic agents, help to identify the optimal time window and the appropriate dosage of the different therapeutic agents, assist in monitoring the effects of such treatments, and provide functional information for adjusting the therapeutic regimens over time in an interactive basis [1]. Since imaging can potentially provide morphologic, functional and molecular information in a spatially and temporally resolved manner, many investigators have incorporated imaging into pre-clinical studies and clinical trials of angiogenesis therapies. Many important aspects of angiogenesis imaging are covered by the superb collection of articles in this special issue but I would like to highlight several important issues that cannot be overemphasized. In the past, diagnostic imaging tests were designed to be stand alone investigations with specialized image acquisition, analysis and display. It is important that we do not utilize diagnostic imaging tests in this way, but rather we should use imaging tests in combination to maximize relevant information. For example, by combining the rich metabolic and functional information gained from position emission tomography (PET) with the morphologic information provided by CT, new information can be gained that cannot be obtained with each modality alone. This is only the beginning of what may prove to be a significant paradigm shift in medical imaging device design and manufacturing. In recent years there have been rapid developments of various high throughput tissue analysis techniques such as functional genomics, proteomics and tissue arrays. These new technologies allow us to quantify the expression level of virtually every gene in the genome as well as many of the proteins from tissue samples. It seems logical to first characterize the target tissues with an appropriate array of imaging tests and then to use image guidance for tissue procurement so that we can correlate the imaging phenotypes with tissue analysis data. This ‘‘image-guided tissue analysis’’ approach should allow us to further our understanding of the complex interactions of pathological processes and host responses in a spatially and temporally resolved manner that affect non-invasive image contrast. This type of information could then be used for designing appropriate therapeutic regimens for individual patients at specific times [2, 3]. This type of information could also be used to guide development of ‘‘target-specific’’ imaging probes so negating the need for invasive biopsies in the future. Co-developing a molecular imaging agent with a targeted therapeutic angiogenic agent may facilitate ‘‘personalized treatment’’. This concept is not new; the FDA approved ibritumomab tiuxetan (Zevalin; IDEC Pharmaceuticals, Cambridge, MA), a therapeutic regimen for treatment of relapsed or refractory low grade, follicular or transformed B-cell non-Hodgkin’s lymphoma. The paradigm here is the use of indium-111 labelled Zevalin scanning mainly for dosimetry purposes prior to yittrium-90 labelled Zevalin treatment. At the National Institutes of Health (NIH) we are working on a nanoparticle delivery platform that can potentially deliver both imaging and therapeutic agents to endothelial targets. Using a vascular targeted imaging agent for selecting patients to be treated and for monitoring response with the therapeutic agents delivered via the same delivery vehicle satisfies the requirements for ‘‘personalized treatment’’ [4–6]. We should all work on other integrative approaches where developing an imaging and therapeutic agents can be synergistic. In summary, much work has been done to try to establish imaging tests as biomarkers and even ‘‘surrogate endpoints’’ for various angiogenesis therapies. However, initial results have been mixed (see articles by Galbraith and Padhani in this journal issue) probably due to a combination of factors the most important of which may be the lack of understanding of the biological and molecular basis for the different imaging phenotypes in different disease environments. With the increased scientific momentum in the field of angiogenesis, imaging scientists should strive to exploit both imaging and nonimaging tools so that the full potential of imaging can be realised.