VEGF-driven PET imaging of tumor angiogenesis

DESCRIPTION (provided by applicant): The overall goal of this project is development of targeted PET probes for molecular imaging of receptors for vascular endothelial growth factor (VEGF), a crucial drug target in oncology patients. Tumor imaging with FDG, as well as imaging of tumor vasculature with blood pool contrast agents, provides important general information on tumor size and metabolic activity of tumor cells. However, molecular imaging of specific drug targets would greatly facilitate development of new drugs, rational selection of patients, and development of personalized treatment regiments. In our original submission on 12/01/2005 and the first resubmission on 04/01/2006 we proposed to synthesize and test in vivoa VEGF-based Cu PET radiotracer for imaging 64 VEGF receptors in tumor vasculature. By now, our lead radiotracer, named scVEGF/Cu, has been developed and validated in mouse tumor models. scVEGF/Cu selectively and specifically image VEGF receptors in tumor vasculature. In contrast, either functionally inactivated or blocked scVEGF/Cu display only negligible accumulation in tumor. scVEGF/Cu provides excellent PET images, displays unusually low non-specific organ uptake, essentially does not degrade or dissociate through the clearance time, and lacks detectable tumor-stimulating effects. Finally, a fluorescent scVEGF-based probe colocalizes with endothelial cell markers in vivo. In view of these results, we can now proceed with validation of scVEGF/Cu for a potential clinical use. Since the goal of molecular PET imaging of VEGF receptors is to characterize their prevalence in individual patients, it is now necessary to establish how imaging with scVEGF/Cu is linked to VEGF receptor prevalence and what roles play endogenous tumor VEGF and tumor perfusion in uptake of radiotracer. We propose an integrated experimental approach to answer these questions that are crucial for understanding how scVEGF/Cu radiotracer can be used in individual patients for characterizing of VEGF receptor prevalence. Accomplishing Specific Aims of this proposal will provide a rational basis for GMP-production, formal toxicology and initial clinical trials in Phase II of this project.