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Theranostics 2014; 4(3):267-279. doi:10.7150/thno.7323 This issue Cite

Research Paper

Imaging the Urokinase Plasminongen Activator Receptor in Preclinical Breast Cancer Models of Acquired Drug Resistance

Aaron M. LeBeau^1✉, Natalia Sevillano², Mandy L. King³, Sai Duriseti², Stephanie T. Murphy¹, Charles S. Craik², Laura L. Murphy³, Henry F. VanBrocklin¹

1. Center for Molecular and Functional Imaging, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA 94118.
2. Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94118.
3. Department of Physiology, Southern Illinois University School of Medicine, Carbondale, IL 62901.

✉ Corresponding author: Aaron M. LeBeau, Ph.D. Department of Radiology and Biomedical Imaging, University of California, San Francisco, 185 Berry Street, Suite 350, San Francisco, CA, 94143-2280. Phone: (415) 476-8147 Fax: (415) 514-8242 Email: Aaron.Lebeauedu. More

Abstract

Subtype-targeted therapies can have a dramatic impact on improving the quality and quantity of life for women suffering from breast cancer. Despite an initial therapeutic response, cancer recurrence and acquired drug-resistance are commonplace. Non-invasive imaging probes that identify drug-resistant lesions are urgently needed to aid in the development of novel drugs and the effective utilization of established therapies for breast cancer. The protease receptor urokinase plasminogen activator receptor (uPAR) is a target that can be exploited for non-invasive imaging. The expression of uPAR has been associated with phenotypically aggressive breast cancer and acquired drug-resistance. Acquired drug-resistance was modeled in cell lines from two different breast cancer subtypes, the uPAR negative luminal A subtype and the uPAR positive triple negative subtype cell line MDA-MB-231. MCF-7 cells, cultured to be resistant to tamoxifen (MCF-7 TamR), were found to significantly over-express uPAR compared to the parental cell line. uPAR expression was maintained when resistance was modeled in triple-negative breast cancer by generating doxorubicin and paclitaxel resistant MDA-MB-231 cells (MDA-MB-231 DoxR and MDA-MB-231 TaxR). Using the antagonistic uPAR antibody 2G10, uPAR was imaged in vivo by near-infrared (NIR) optical imaging and ¹¹¹In-single photon emission computed tomography (SPECT). Tumor uptake of the ¹¹¹In-SPECT probe was high in the three drug-resistant xenografts (> 46 %ID/g) and minimal in uPAR negative xenografts at 72 hours post-injection. This preclinical study demonstrates that uPAR can be targeted for imaging breast cancer models of acquired resistance leading to potential clinical applications.

Keywords: urokinase plasminogen activator receptor, single-photon emission computed tomography, human antibody, drug-resistant breast cancer, tamoxifen resistance, phage display.

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