PET/CT Using New Imaging Agent an Improvement over Current Standard

Scientists have developed a new imaging agent that can be used in scanning for tumors and provides a much clearer and more precise image than existing methods. The discovery with the potential to revolutionize preclinical cancer research and clinical diagnostic practice, makes use of compounds that have already been approved for treating patients: the anticancer drug bevacizumab (Avastin) and copper-64, a radioactive copper nuclide, which is approved by the US Food and Drug Administration (FDA) for some clinical trials.

Dr. Zheng Jim Wang, director of molecular imaging at MPI Research, Inc. (Mattawan, MI, USA) and an adjunct assistant professor at University of Texas Health Science Center at San Antonio (TX, USA), reported at the 20th EORTC-(European Organization for Research and Treatment of Cancer)-[U.S.] National Institute of Cancer (NCI)-AACR (American Association for Cancer Research) Symposium on Molecular Targets and Cancer Therapeutics in Geneva, Switzerland, on October 22, 2008, that he and his colleagues had attached bevacizumab to a molecule called DOTA (a cyclic compound) and tagged it with a radioactive tracer, copper-64 (64Cu). Bevacizumab is an antibody that targets vascular endothelial growth factor (VEGF), a signaling protein released by tumor cells and which plays an important role in angiogenesis (the process by which a growing tumor creates its own blood supply). Currently, bevacizumab is being used to treat patients with advanced colorectal cancer and is being evaluated in several other metastatic cancers.

When the researchers injected the compound (64Cu-bevacizumab) into mice with breast, lung, and pancreatic cancers and then used positron emission tomography/computed tomography (PET/CT) imaging to scan the animals, they found that it successfully targeted the cancer cells, accumulating in high concentrations in the tumors, and that it enabled clear and well-defined images of the tumors to be detected during scanning.

When compared with images of the same tumors in the same animals taken the day before, using the current gold standard imaging probe for tumors (18-fluorodeooxylucose [18FDG]), the scientists found that not only were the 64Cu-bevacizumab images better, but also that they could detect tumors in earlier stages and at smaller sizes than with 18FDG. Moreover, the 64Cu-bevacizumab images had none of the conventional "hot spots” that tend to appear in 18FDG images and which affect the accuracy of the imaging. Hot spots occur where the compound has accumulated not just in tumors but also in key organs (such as the heart, brain, kidneys and bladder), which give false-positive signals.

Dr. Wang, said, "Our collaborative research reveals, and verifies a new imaging agent for the next-generation of tumor detection imaging probes. [The tracer] 64Cu-bevacizumab is highly sensitive in pancreatic, lung, and breast, cancer models, detecting tumors earlier than 18FDG, with much better contrast between the tumor and the surrounding tissue and with fewer non-tumor-related hot spots. Because it uses different biologic mechanisms compared with 18FDG, it could detect a broader range of tumor types than 18FDG. Since bevacizumab has been approved by the FDA for treating patients and copper-64 for clinical trials, the conjugated compound has a much higher chance of being applied to clinical use faster than other, newly developed bimolecular compounds. VEGF-related angiogenesis is almost a universal phenomenon for most types of solid tumors. We are testing this probe in different cancers [lung, pancreatic, ovarian, prostate, breast, and colon cancer] and bone metastasis models to verify our assumption. Once it's been verified and validated, we are planning to test it in clinical trials.”

Dr. Wang and his group are the first to show that it is possible to use bevacizumab as a diagnostic imaging agent to detect early tumors in animal models and that it is better than the gold standard 18FDG. However, he said that when he and his colleagues first started the project, some scientists and doctors in the cancer field did not believe their theory could work because VEGF is diffusible and breaks down very quickly. "They highly doubted the research goal and some of them refused to believe the first imaging result, which was thought too good to be true," he said.

The group persisted, and in 2007, another research group in The Netherlands independently published similar results in an ovarian tumor model. "Eventually we found out that while some types of VEGF are diffusible, other types of VEGF are located at the tumor cell surface and very near the extracellular matrix. That is why the radiolabeled bevacizumab targets VEGF on the angiogenesis site around the tumor and demonstrates excellent imaging of the tumor. Since we are targeting early stage of angiogenesis we are able to see the tumor when it is still very small or in other words, in a very early stage,” remarked Dr. Wang.

Once researchers have obtained the necessary confirmation of their results in additional studies and clinical trials, imaging with 64Cu-bevacizumab could be used in both pre-clinical and clinical work. "In clinical work with patients, the superior imaging will enable us to detect and diagnose tumors at earlier stages, to monitor the effects of therapy on the patients' cancers, and, because the contour of tumor is so much clearer with 64Cu-bevacizumab, it will help physicians to decide the size of the tumor and may be able to help the radiation oncologist decide the clinical treatment volume,” stated Dr. Wang.

Dr. Wang reported that it was possible that other, targeted cancer therapies could be used for imaging in a similar way, but this depended on the type, biologic distribution, specificity, and pharmacokinetics of the drug. "Some targeted drugs may be too specific to be used as the first-line imaging agent for the diagnosis of a broad spectrum of cancers. However, once the cancer is detected by the first-line imaging agent, other targeted cancer therapies may be useful as imaging agents when monitoring whether the drugs are sufficiently targeted at the tumor site. This will offer valuable information in deciding treatment strategy, such as dosing optimization and personalized medicine.”

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