The cell adhesion molecule integrin ?v?3 is up-regulated during tumor angiogenesis and metastasis. The unique and/or overexpression of this G-protein receptor on sprouting endothelial cells in growing tumors and on tumor cells of various origins provides a robust platform for application of anti-angiogenic and antimetastatic strategies. We have previously developed a series of mono-, di- and multimeric RGD peptide radiotracers for positron emission tomography (PET) imaging of tumor integrin expression. In particular, tetrameric and octameric RGD peptide tracers have demonstrated extraordinarily high and persistent integrin specific tumor uptake and favorable in vivo kinetics. Both 64Cu- and 90Y-labled RGD tetramers were also effective in slowing breast cancer tumor growth. The purpose of this proposal is to develop a multimeric RGD peptide library, from which we expect to identify highly effective integrin-specific agents for diagnosis and treatment of localized and metastasized breast cancer. Our research plan will extend this effort and focus on the following four areas: 1) we will screen a number of orthotopic and spontaneous breast cancer models in order to identify a highly integrin positive tumor model for RGD peptide probe evaluation;2) we will perform a systematic structure-activity relationship (SAR) study to identify more potent multimeric RGD peptides for 64Cu and 86Y labeling for breast cancer targeting;3) we will evaluate the capabilities of 64Cu and 86Y-labeled multimeric RGD peptides to visualize and quantify integrin expression in vivo and to detect lung metastasis in breast cancer xenograft models;4) we will determine the internal radiation dosimetry and evaluate the treatment efficacy of 64Cu- and 90Y-labeled multimeric RGD peptides in primary tumor and lung metastasis of breast cancer models. The effect of both single dose and multiple dose administration will be tested. The success of this project will lead to rapid translation into clinical trials for tumor detection and treatment. The ability to non-invasively visualize and quantify ?v?3 integrin expression level will provide new opportunities to document tumor (tumor cells and sprouting tumor vasculature) receptor expression, more appropriately select patients considered for anti-integrin treatment and monitor treatment efficacy in integrin-positive patients. The same ligands labeled with therapeutic isotopes will allow targeted internal radiotherapy of integrin positive tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA119053-04
Application #
7906713
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Tandon, Pushpa
Project Start
2007-09-20
Project End
2011-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
4
Fiscal Year
2010
Total Cost
$238,119
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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