Angiogenesis imaging

血管生成成像

• 批准号: 7965556
• 负责人: peter L choyke
• 金额: $ 78.75万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7965556
• 关键词: Acids; Address; Angiogenesis Inhibitors; Area; Beds; Binding; Biological Markers; Bolus Infusion; Brain Neoplasms; CCR; Cell surface; Chemistry; Clinic; Clinical; Clinical Research; Colon Carcinoma; Color; Communities; Computer software; Contrast Media; Discipline of Nuclear Medicine; Dose; Effectiveness; Endothelial Cells; Ensure; Extramural Activities; Functional Imaging; Glioblastoma; Growth; Healthcare; Hospitals; Image; Imaging Techniques; Inflammatory; Institution; Integrins; Intramural Research Program; Label; Laboratories; Left; Lesion; Ligands; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of lung; Maps; Measurement; Measures; Medical Oncology; Methods; Modeling; Molecular Target; Molecular Weight; Monitor; Mus; Nature; Neoplasms; Nurse Practitioners; Nursing Research; Online Systems; Patients; Performance; Permeability; Pharmaceutical Preparations; Physicians; Physiology; Positron-Emission Tomography; Process; Proliferating; Protocols documentation; Publications; Quantitative Autoradiography; Radioisotopes; Radiolabeled; Radiology Specialty; Rattus; Research; Research Personnel; Role; Sarin; Scientist; Services; Standardization; System; Testing; Time; Tumor Angiogenesis; Tumor Necrosis Factor-alpha; United States National Institutes of Health; Validation; Vascular Permeabilities; Work; Yang; angiogenesis; base; bevacizumab; cancer imaging; chemotherapy; design; experience; imaging modality; improved; in vivo; insight; interest; malignant breast neoplasm; molecular imaging; neuro-oncology; novel; optical imaging; pre-clinical; pre-clinical research; programs; radiologist; radiotracer; research study; response; tool; treatment strategy; tumor; validation studies

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.

血管生成血管生成的成像是癌症生长和扩散的重要过程。对于CCR中的科学家和临床医生来说，这是一个非常感兴趣的话题，他们利用抗血管生成策略进行治疗，因此，MIP在其靶向肿瘤成像程序中解决血管生成的重要性。在这里，我们描述了MIP中血管生成成像的临床前和临床方面。临床前研究有两种用于血管生成成像的方法：生理或功能研究，研究了肿瘤内血管的流动和渗透率动力学以及分子靶向方法。 我们已经研究了这两个方面。 MIP在动态对比度增强MRI（DCE-MRI）的性能方面发展了专业知识，该MRI（DCE-MRI）具有低分子量和大分子对比剂（1-3）。这是一个看似直接的测试，其中一磁性对比剂的推注之后是图像的快速获取。然后分析图像，并得出反映脉管系统生理的曲线拟合参数。 有趣的是，虽然很受欢迎，但与其他众所周知的测量血管渗透性的方法相比，这种方法几乎没有验证。我们已经与UCSF的Donald McDonalds Lab一起进行了超微结构研究（4）。 我们进行了一项鼠类研究，在其中比较了放射性标记（14C）的渗透率（使用脑肿瘤模型中的DCE-MRI使用定量自显影术（QAR）（5）。我们发现QAR结果与参数KTRAN之间的良好相关性与dce-Mri衍生的参数相关。血管生成）（6）。在过去的一年中，我们使用环化RGD开发了靶向的整联蛋白成像（光学和放射性核素）。这项工作可能导致靶向成像剂直接可视化血管生成血管。但是，由于模型不足，在这一领域的工作可能令人失望。正在寻求新的目标成像代理，以进一步追求这项工作。临床研究MIP为临床中心的研究人员提供了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中的一个临床研究员之一识别目标病变，并确保每次患者返回时都会进行适当的研究。该研究员还为研究目的提供了结果。 MIP正在为观察各种抗血管生成剂的CCR研究人员提供5个主动方案。从本质上讲，这项工作很困难，出版物的累积很慢，但是在过去的一年中，有两个出版物是Swain博士在离开NCI之前进行的乳腺癌试验（7、8）。这些表明，贝伐单抗反应者的血管通透性发生了深刻的变化，然后进行了高剂量强化化疗。将DCE-MRI的作用与研究的其他生物标志物进行了比较，并且发现它是预测标记中最有用的。 MIP还将使用针对AVB3和AVB5整联蛋白的宠物剂对Howard Fine博士进行研究。这个标记为18F的宠物代理商是由GE Healthcare制造的，并向NCI提供了用于试用目的。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），一位身体放射科医生（Peter Choyke），一名神经放射学家（Dima Hammoud）（Dima Hammoud），以及以护士从业者和研究护士的形式提供支持的员工，我们已经准备好了这个机会，以前的机会是善良的（当前的人）。 Gianconne博士（医学肿瘤科）分别在胶质母细胞瘤和肺癌中开发合适的成像试验，以测试这种新型血管生成剂。 Brechbiel，M。和Choyke，P。L.成像肿瘤血管生成的大分子MRI对比剂。基于树枝状聚合物的磁共振成像对比剂：新的双功能二乙基三乙烯乙乙酸配体和非水的结合化学。 J Med Chem，50：3185-3193，2007。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。前Biosci，12：3601-3616，2007。在RG2大鼠脑肿瘤模型中使用定量放射摄影的测量。 Neoplasia，9：546-555，2007。6。投资Radiol，41：691-696，2006年。7。Wedam，S.B.，Low，J.A.，J.A. Koeppen，H.，Sherman，M.，Zujewski，J.，Camphausen，K.，Chen，H。和Swain，S.M。Bevacizumab对炎症性和局部晚期乳腺癌患者的抗血管生成和抗肿瘤作用。 J Clin Oncol，24：769-777，2006。8。Thukral，A.，Thomasson，D.M.，Chow，C.K.贝伐单抗初始经验。放射学，244：727-735，2007。