The utility of Positron Emission Tomography (PET) in the detection of cancer began with the radiopharmaceutical 2-[18F]fluoro-2-deoxyglucose (FDG) used for measuring altered cellular metabolism. Specific radioligands are being developed to allow non-invasive analysis of protein expression to further characterize tumors. One protein that has been identified as a promising target is the Peripheral Benzodiazepine Receptor (PBR). PBR expression is up-regulated in several cancers, and in many there has been a correlation drawn between increased malignancy and protein expression levels. Therefore, developing PET methodologies to apply for PBR imaging could be an important step in understanding individual tumors as we move toward an age of personalized medicine. This dissertation investigates the potential utility of two radioligands specific for PBR, and compares the radioligands to radiopharmaceuticals that map metabolism (FDG) and proliferation (3'-[18F]fluoro-L-thymidine, FLT). The research has two specific aims: (1) to compare PBR expression with measures of cellular proliferation and aggression; (2) to directly compare radioligand localization in vivo to tumor sites in mouse xenograft model studies. In vitro cell studies indicate a correlation between PBR expression and markers of aggression, but not proliferation. Using PET imaging and biodistribution, breast cancer xenografts with a breadth of PBR expression showed no significant uptake of PBR specific radioligands. However, radiopharmaceuticals targeting proliferation by metabolism and DNA synthesis showed greater differences in uptake between cell lines. The data obtained from these studies demonstrate a limitation to the translation of PBR imaging for personalized medicine, because the ubiquitous expression of the protein throughout the body creates challenges that will be difficult to overcome. Expression of PBR in non-target organs reduces the quantity of radiopharmaceutical that is available for tumor uptake, and the extent of non-tumor uptake of radiopharmaceuticals with affinity for PBR exceeds that of tumors. These results suggest that non-invasive imaging techniques to assay tumor PBR expression in vivo have limited potential for clinical applications.
|Commitee:||Covey, Douglas, Harbour, William, Mach, Robert, Welch, Michael|
|School:||Washington University in St. Louis|
|Department:||Biology & Biomedical Sciences (Biochemistry)|
|School Location:||United States -- Missouri|
|Source:||DAI-B 70/07, Dissertation Abstracts International|
|Keywords:||PBR, PET, Peripheral benzodiazepine receptor, Tumors|
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