Imaging of Angiogenesis Angiogenesis is an important process in the growth and spread of cancer. It is a topic of great interest to scientists and clinicians in the CCR who are utilizing anti-angiogenic strategies for treatment and therefore, it is of importance that the MIP address angiogenesis in its program of targeted tumor imaging. Here, we describe the pre-clinical and clinical aspects of angiogenesis imaging in MIP. Pre-Clinical Research There are two approaches to angiogenesis imaging: physiologic or functional studies that investigate the flow and permeability dynamics of vessels within tumors and a molecular targeted approach. We have investigated both aspects. The MIP has developed expertise in the performance of dynamic contrast enhanced MRI (DCE-MRI)with low molecular weight and macromolecular contrast agents(1-3). This is a seemingly straightforward test in which a bolus of a paramagnetic contrast agent is followed by the rapid acquisition of images. The images are then analyzed and curve fitting parameters are derived that reflect the physiology of the vasculature. Interestingly, while popular, there has been little validation of this method compared to other well known methods of measuring vessel permeability. We have conducted ultrastructure studies in conjunction with Donald McDonalds lab in UCSF(4). We conducted an murine study in which radiolabeled (14C) permeability agent was compared (using Quantitative AutoRadiography (QAR) with DCE-MRI in a brain tumor model(5). We found excellent correlation between the QAR results and the parameter Ktrans which is derived from DCE-MRI. We have also performed validation studies in treatment models involving TNFalpha (6). Over the past year we have developed targeted integrin imaging (optical and radionuclide) using cyclized RGD (cRGD). This work could result in a targeted imaging agent for directly visualizing angiogenic vessels. New targeted imaging agents are being sought to further pursue this work. Additionally, in collaboration with Brad St Croix, we have labeled an antibody against TEM8 which is highly expressed in angiogenic vessels and appears highly specific. This antibody is being developed as a therapeutic agent by a major Pharma company. We have labeled this antibody with both Br76 and Zr89 in order to document its areas of increased uptake. Interestingly, because this is an endothelial marker it is difficult to measure in vitro. Thus, in vivo measurement is a requirement. Preliminary data suggests that the agent is not only sensitive for angiogenesis but it also can be inhibited by therapeutic levels of the antibody. Moreover, to make a more practical imaging agent as a potential companion diagnostic, we have developed antibody fragments with Gary Griffiths lab. Thse should allow more rapid imaging than is possible with full antibodies. Recently we have discovered a simple way to label albumin with F18, a PET emitter. Early results suggest a highly promising future for this method of assessing blood volume in vivo and quantitatively. Clinical studies The MIP provides a DCE-MRI service to investigators in the Clinical Center. This is now considered a routine study at NIH due to our efforts. One of the clinical fellows in MIP, identifies a target lesion and ensures that the proper study is performed each time the patient returns. The fellow also provides results to the investigators for research purposes. The MIP is providing this service to 5 active protocols by CCR investigators who are looking at various anti-angiogenic agents. Such work, by its nature, is difficult and publications have been slow to accrue, however in the past years two publications have appeared from a breast cancer trial (7, 8). These demonstrate profound changes in vessel permeability in responders to Bevacizumab followed by high dose intensive chemotherapy. The role of DCE-MRI was compared to other biomarkers that were studied and it was found to be among the more useful of the predictive markers. The MIP is also conducting a study with Dr. Wyndham Wilson using a PET agent that targets the AvB3 and AvB5 integrins. This 18F labeled PET agent is made by GE Healthcare and is being offered to NCI for trial purposes. Because we have been able to develop a clinical team (2 nuclear medicine physicians (Karen Kurdziel, Liza Lindenberg), one body radiologist (Peter Choyke), one neuroradiologist (Dima Hammoud) as well as support staff in the form of Nurse Practitioners and Research Nurses, we are prepared to take advantage of this opportunity that would formerly not have been possible. We have initated a proof of principle trial involving 30 patients with this agent, which is named flucilitide. In this trial a single fluciclitide imaging study is performed prior to surgery. The specimen is then analyzed for integrin expression using immunohistochemistry. We have just begun a clinical trial in patients receiving anti-angiogenic therapies (four protocols feed this imaging protocol). In this trial fluciclitide imaging is obtained before and after one cycle of therapy as defined by the treatment protocol. 1. Barrett, T., Brechbiel, M., Bernardo, M., and Choyke, P. L. MRI of tumor angiogenesis. J Magn Reson Imaging, 26: 235-249, 2007. 2. Barrett, T., Kobayashi, H., Brechbiel, M., and Choyke, P. L. Macromolecular MRI contrast agents for imaging tumor angiogenesis. Eur J Radiol, 60: 353-366, 2006. 3. Xu, H., Regino, C. A., Bernardo, M., Koyama, Y., Kobayashi, H., Choyke, P. L., and Brechbiel, M. W. Toward improved syntheses of dendrimer-based magnetic resonance imaging contrast agents: new bifunctional diethylenetriaminepentaacetic acid ligands and nonaqueous conjugation chemistry. J Med Chem, 50: 3185-3193, 2007. 4. Ocak, I., Baluk, P., Barrett, T., McDonald, D. M., and Choyke, P. The biologic basis of in vivo angiogenesis imaging. Front Biosci, 12: 3601-3616, 2007. 5. Ferrier, M. C., Sarin, H., Fung, S. H., Schatlo, B., Pluta, R. M., Gupta, S. N., Choyke, P. L., Oldfield, E. H., Thomasson, D., and Butman, J. A. Validation of dynamic contrast-enhanced magnetic resonance imaging-derived vascular permeability measurements using quantitative autoradiography in the RG2 rat brain tumor model. Neoplasia, 9: 546-555, 2007. 6. Tang, J. S., Choy, G., Bernardo, M., Thomasson, D., Libutti, S. K., and Choyke, P. L. Dynamic contrast-enhanced magnetic resonance imaging in the assessment of early response to tumor necrosis factor alpha in a colon carcinoma model. Invest Radiol, 41: 691-696, 2006. 7. Wedam, S. B., Low, J. A., Yang, S. X., Chow, C. K., Choyke, P., Danforth, D., Hewitt, S. M., Berman, A., Steinberg, S. M., Liewehr, D. J., Plehn, J., Doshi, A., Thomasson, D., McCarthy, N., Koeppen, H., Sherman, M., Zujewski, J., Camphausen, K., Chen, H., and Swain, S. M. Antiangiogenic and antitumor effects of bevacizumab in patients with inflammatory and locally advanced breast cancer. J Clin Oncol, 24: 769-777, 2006. 8. Thukral, A., Thomasson, D. M., Chow, C. K., Eulate, R., Wedam, S. B., Gupta, S. N., Wise, B. J., Steinberg, S. M., Liewehr, D. J., Choyke, P. L., and Swain, S. M. Inflammatory Breast Cancer: Dynamic Contrast-enhanced MR in Patients Receiving Bevacizumab Initial Experience. Radiology, 244: 727-735, 2007.

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Bhutani, M; Turkbey, B; Tan, E et al. (2014) Bone marrow angiogenesis in myeloma and its precursor disease: a prospective clinical trial. Leukemia 28:413-6
Longmire, Michelle R; Ogawa, Mikako; Choyke, Peter L et al. (2014) Dendrimers as high relaxivity MR contrast agents. Wiley Interdiscip Rev Nanomed Nanobiotechnol 6:155-62
Kosaka, Nobuyuki; Mitsunaga, Makoto; Choyke, Peter L et al. (2013) In vivo real-time lymphatic draining using quantum-dot optical imaging in mice. Contrast Media Mol Imaging 8:96-100
Azad, Nilofer; Yu, Minshu; Davidson, Ben et al. (2013) Translational predictive biomarker analysis of the phase 1b sorafenib and bevacizumab study expansion cohort. Mol Cell Proteomics 12:1621-31
Sano, Kohei; Nakajima, Takahito; Choyke, Peter L et al. (2013) Markedly enhanced permeability and retention effects induced by photo-immunotherapy of tumors. ACS Nano 7:717-24
Barrett, Tristan; Ravizzini, Gregory; Choyke, Peter L et al. (2009) Dendrimers in medical nanotechnology. IEEE Eng Med Biol Mag 28:12-22
Padhani, Anwar R; Liu, Guoying; Koh, Dow Mu et al. (2009) Diffusion-weighted magnetic resonance imaging as a cancer biomarker: consensus and recommendations. Neoplasia 11:102-25
Longmire, Michelle; Choyke, Peter L; Kobayashi, Hisataka (2008) Clearance properties of nano-sized particles and molecules as imaging agents: considerations and caveats. Nanomed 3:703-17
Kurdziel, Ka; Ravizzini, G; Croft, By et al. (2008) The evolving role of nuclear molecular imaging in cancer. Expert Opin Med Diagn 2:829-842
Giesel, Frederik L; Choyke, Peter L; Mehndiratta, Amit et al. (2008) Pharmacokinetic analysis of malignant pleural mesothelioma-initial results of tumor microcirculation and its correlation to microvessel density (CD-34). Acad Radiol 15:563-70

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