ZIA BC 010714 (ZIA) | |||
---|---|---|---|
Title | Angiogenesis imaging | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Choyke, Peter | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $454,467 | Project Dates | 10/01/2005 - 00/00/0000 |
Fiscal Year | 2014 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Bioengineering (20.0%) Cancer (100.0%) Nuclear Magnetic Resonance Imaging (NMR) (20.0%) |
Breast (20.0%) Lung (10.0%) |
||
Research Type | |||
Technology Development and/or Marker Discovery Technology and/or Marker Testing in a Clinical Setting |
|||
Abstract | |||
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 predi" |