Abstract 691: Down-regulation of Wnt10b following targeted theranostic nanoparticles in a patient derived xenograft model of triple negative breast cancer
Authors: Miller-Kleinhenz Jasmine , Qian Weiping , O'Regan Ruth , Styblo Toncred , Zelnak Amelia , Wang Andrew , Yang Lily 
Published: May 2015

BACKGROUND: Triple negative breast cancer (TNBC) is a highly heterogeneous and aggressive disease with a poor clinical prognosis. While the primary therapeutic option for TNBC patients is pre-operative neo-adjuvant chemotherapy followed by surgical resection, about 60% of patients develop drug resistance and have a very high incidence of tumor recurrence and poorer prognosis. Given its poor survival and lack of available targeted therapeutics, the development of novel treatment options for chemo-resistant TNBC is critical. Cancer progenitor cells or stem-like cells (CSCs) are generally thought to contribute to the drug-resistant phenotype of TNBC which are typically identified as CD44+/CD24-. CSCs can also rely on activation of stem cell signaling through the Wnt/ β-catenin pathway. Components of the Wnt pathway, including Wnt ligands, have been shown to be over-expressed in human breast cancers.

Our lab has developed urokinase plasminogen activator receptor (uPAR) targeted theranostic magnetic iron oxide nanoparticles (IONPs) carrying therapeutic agents that are clinically beneficial to TNBC patients such as doxorubicin (Dox). uPAR is an ideal target due to its high expression in malignant tumors including aggressive breast cancer tissues and tumor stromal cells that are enriched in TNBC tissues.

METHODS: We generated patient derived xenografts of drug-resistant TNBC for testing the therapeutic efficacy of uPAR-targeted nanoparticle-drugs from tumor fragments from patients obtained from an ongoing Phase II clinical trial at Winship Cancer Institute. Histological analysis of post-chemotherapy TNBC with or without uPAR-targeted IONP-Dox was conducted using immunohistochemistry and immunofluorescence techniques.

RESULTS: We have previously reported that treatment with uPAR-targeted IONP-Dox caused tumor growth inhibition following systemic delivery. We further investigated the effect of uPAR-targeted IONP on Wnt10b, a ligand of the Wnt signaling pathway. We observed that uPAR-targeted-IONP-Dox treatment decreases Wnt10b expression relative to the untreated and conventional Dox groups. We also investigated the level of CD44 expression, which is a target gene of the Wnt signaling pathway. We observed that Wnt10b and CD44 expression was co-localized and that treatment with uPAR-targeted IONP-Dox decreased the level of CD44 expression that is comparable to the level of decrease in Wnt10b expression.

CONCLUSION: Our findings show that uPAR-targeted theranostic IONP can effectively target the Wnt activated CSC population. It is likely that uPAR expressing tumor cells are potential drug resistant cell populations with breast cancer stem-like cell properties. Our results support further investigation of theranostic nanoparticles as a viable therapeutic approach to overcome drug resistance in TNBC.

Citation Format: Jasmine Miller-Kleinhenz, Weiping Qian, Ruth O'Regan, Toncred Styblo, Amelia Zelnak, Andrew Wang, Lily Yang. Down-regulation of Wnt10b following targeted theranostic nanoparticles in a patient derived xenograft model of triple negative breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 691. doi:10.1158/1538-7445.AM2014-691