Vascular endothelial growth factor (VEGF) receptors VEGFR-1 (FLT-1) and VEGFR-2 (KDR/Flk-1) are prime targets for anti-angiogenic therapeutics because they are up-regulated on tumor vascular endothelium but not surrounding normal quiescent vessels. Studies have shown that the KDR receptor is primarily responsible for the pro-angiogenic effects of VEGF in solid tumors. We found that 64Cu-DOAT-VEGF121 was able to detect VEGFR expression in vivo. However, imaging probes derived from wild-type VEGF121 tend to have prominent renal uptake and subsequently high radiation burden to this organ in which VEGFR-1 expression is considerably high. We have also developed a D63AE64AE67A mutant of VEGF121 (VEGFDEE), which binds preferably to VEGFR-2 to VEGFR-1. 64Cu-DOTA-VEGFDEE has comparable tumor targeting ability as 64Cu- DOTA-VEGF121 but much reduced renal uptake. In this proposal, we will extend this effort and perform a systemic study to identify appropriate VEGF mutant sequences with further reduced VEGFR-1 and improved VEGFR-2 binding to minimize VEGFR-1 specific kidney activity accumulation. The overarching hypotheses are that 1) VEGFR-2 is a viable target for cancer imaging;and 2) visualization and quantification of tumor angiogenesis by PET imaging of VEGFR-2 expression will allow for prediction and monitoring anti-angiogenic treatment efficacy. We will first develop VEGF121 variants which specifically bind to VEGFR-2 by means of phage display technique. We will then label VEGFR-2 specific mutants with 64Cu for PET imaging of VEGFR-2. Finally, we will quantify VEGFR-2 expression in both subcutaneous and orthotopic brain tumor models through multimodality imaging techniques. Targeted VEGF receptor imaging may be beneficial to standard clinical assessment of flow or perfusion by providing information on the degree of hypoxic stress experienced by living tissue. Although the proposed project is mainly focused on visualization and quantification of cancer Flk-1/KDR expression levels, the same probes developed here can be used for the implementation and evaluation of angiogenesis involved in other pathological processes such as diabetic retinopathy, rheumatoid arthritis, and atherosclerotic cardiovascular disease. In addition, successful development of VEGF-driven PET imaging could also serve as a paradigm for the assessment of therapeutic angiogenesis. The optimal method for evaluating therapeutic response to angiogenic interventions will also permit evaluation of the therapeutic effects of appropriate angiogenic strategies.

Public Health Relevance

Vascular endothelial growth factor (VEGF) receptors VEGFR-1 (FLT-1) and VEGFR-2 (KDR/Flk-1) are prime targets for anti-angiogenic therapeutics because they are up-regulated on tumor vascular endothelium but not surrounding normal quiescent vessels. In this project we propose to develop a VEGFR-2 specific positron emission tomography (PET) imaging probe that can be used to visualize and quantify VEGFR-2 level in living subjects. The success of this project will allow translation of the new imaging probe into clinic for lesion detection and monitoring therapeutic response.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
4R01CA128908-03
Application #
8192928
Study Section
Special Emphasis Panel (ZRG1-MEDI-A (09))
Program Officer
Tandon, Pushpa
Project Start
2009-05-24
Project End
2013-03-30
Budget Start
2011-05-01
Budget End
2013-03-30
Support Year
3
Fiscal Year
2011
Total Cost
$323,059
Indirect Cost
Name
Stanford University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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