Angiogenesis imaging

血管生成是肿瘤生长和扩散的重要过程。这是CCR中利用抗血管生成策略进行治疗的科学家和临床医生非常感兴趣的话题，因此，MIP在其靶向肿瘤成像计划中解决血管生成问题非常重要。在这里，我们描述临床前和临床方面的血管生成成像在MIP。血管生成成像有两种方法：研究肿瘤内血管流动和渗透动力学的生理或功能研究和分子靶向方法。我们对这两个方面都进行了调查。MIP在低分子量和大分子造影剂的动态对比增强MRI （DCE-MRI）性能方面发展了专业知识（1-3）。这是一种看似简单的测试，其中一剂顺磁造影剂之后是快速获取图像。然后对图像进行分析，并推导出反映脉管系统生理的曲线拟合参数。有趣的是，虽然这种方法很流行，但与其他已知的测量血管渗透率的方法相比，这种方法的有效性很少。我们与UCSF的Donald mcdonald实验室合作进行了超微结构研究(4)。我们进行了一项小鼠研究，在脑肿瘤模型中（使用定量放射自显影（QAR）与DCE-MRI）比较了放射性标记（14C）渗透性剂(5)。我们发现QAR结果与DCE-MRI得出的参数Ktrans之间存在良好的相关性。我们还与Steve Libuttis血管生成实验室合作，在涉及TNFalpha的治疗模型中进行了验证研究(6)。在过去的一年里，我们利用环化RGD开发了靶向整合素成像（光学和放射性核素）。这项工作可能会产生一种直接可视化血管生成血管的靶向显像剂。然而，这一领域的工作令人失望，可能是由于模型不完善。新的靶向显像剂正在寻求进一步开展这项工作。临床研究MIP为临床中心的研究人员提供DCE-MRI服务。由于我们的努力，这现在被认为是NIH的常规研究。MIP的一名临床研究员确定目标病变，并确保每次患者返回时都进行适当的研究。研究员还为研究人员提供研究结果。MIP正在为正在研究各种抗血管生成药物的CCR研究人员的5个活跃方案提供这项服务。这样的工作，就其性质而言，是困难的，出版物积累缓慢，然而在过去的一年中，两篇关于Swain博士在离开NCI之前进行的乳腺癌试验的出版物出现了（7,8）。这些结果表明，在贝伐单抗应答者接受高剂量强化化疗后，血管通透性发生了深刻的变化。将DCE-MRI的作用与其他已研究的生物标志物进行比较，发现它是更有用的预测标志物之一。MIP还将与Howard Fine博士一起进行一项研究，使用针对AvB3和AvB5整合素的PET剂。这种18F标记的PET试剂由GE医疗制造，并提供给NCI用于试验目的。因为我们已经能够建立一个临床团队（2名核医学医生（Karen Kurdziel, Greg Ravizzini）， 1名全身放射科医生（Peter Choyke）， 1名神经放射科医生（Dima Hammoud），以及以护士执业和研究护士形式的支持人员），我们准备利用这个以前不可能的机会。我们目前正与GE、Fine博士（神经肿瘤学分支）和Gianconne博士（医学肿瘤学分支）合作，分别在胶质母细胞瘤和肺癌中开展合适的成像试验，以测试这种新型血管生成剂。1. Barrett， T., Brechbiel， M., Bernardo， M.和Choyke， P. L.肿瘤血管生成的MRI。中国生物医学工程学报，26(2):559 - 559,2007。2. Barrett， T., Kobayashi， H., Brechbiel， M.和Choyke， P. L.大分子MRI造影剂在肿瘤血管生成成像中的应用。中华放射学杂志，2006,31(2):353-366。3. Xu， H., Regino， C. A., Bernardo， M., Koyama， Y., Kobayashi， H., Choyke， P. L.，和Brechbiel， M. W.改进树突基磁共振成像造影剂的合成：新的双功能二乙烯三胺五乙酸配体和非水偶联化学。中华医学杂志，2009,35(3):385 - 393。4. Ocak， I., Baluk， P., Barrett， T., McDonald， D. M.和Choyke， P.：体内血管生成成像的生物学基础。生物科学进展，2009,31(2):391 - 396。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.，和Butman， J. A.在RG2大鼠脑肿瘤模型中使用定量放射自显像技术验证动态对比增强磁共振成像衍生血管通透性测量。中国生物医学工程学报，2009,31(2):546-555。6. Tang， J. S., Choy， G., Bernardo， M., Thomasson， D., Libutti， S. K.和Choyke， P. L.动态对比增强磁共振成像评估结肠癌模型中肿瘤坏死因子α的早期反应。中国生物医学工程学报，2006,31(1):691-696。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., Swain， S. M.贝伐单抗在炎性和局部晚期乳腺癌患者中的抗血管生成和抗肿瘤作用。中华临床医学杂志，24(4):769- 779,2006。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, Swain， S. M.炎症性乳腺癌：接受贝伐单抗初始经验患者的动态对比增强MR。中华放射学杂志，2004,24(4):727-735。

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 in conjunction with Steve Libuttis laboratory of Angiogenesis)(6). Over the past year we have developed targeted integrin imaging (optical and radionuclide) using cyclized RGD. This work could result in a targeted imaging agent for directly visualizing angiogenic vessels. However, work in this area has been disappointing probably owing to inadequate models. New targeted imaging agents are being sought to further pursue this work. 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 year two publications have appeared from a breast cancer trial conducted by Dr. Swain before she left NCI(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 about to conduct a study with Dr. Howard Fine 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, Greg Ravizzini), 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 are currently working with GE and Dr. Fine (Neurooncology Branch) and Dr. Gianconne (Medical Oncology Branch) to develop suitable imaging trials in glioblastoma and lung cancer respectively to test this novel angiogenesis agent. 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.