The goal of this project is to develop innovative image-guided EMT inhibition by targeting the proteins in the key biological event associated with metastasis using RNAi to effectively treat metastatic BC. Metastatic breast cancer is the leading cause of the premature deaths of women diagnosed with the disease in the United States. Currently, there are limited treatment options for the patients whose breast cancer becomes multidrug resistance and relapsed disease. Epithelial-mesenchymal transition (EMT) is a key biological event associated with breast cancer metastasis and multidrug resistance. We have identified several markers of breast cancer EMT for imaging metastatic breast cancer and for effective treatment of metastatic breast cancer by inhibiting cancer cell EMT and resensitizing the cells to chemotherapy under imaging guidance. In this project, we will develop molecular MRI and DCE-MRI to direct the inhibition of BC EMT using targeted lipid siRNA nanoparticles in treating metastatic BC. We will develop targeted multifunctional lipid siRNA delivery systems to down-regulate the expression of key proteins that promote cancer cell EMT for effective inhibition of BC EMT and treatment of metastatic BC alone and in combination with chemotherapy under imaging guidance. Non-invasive and timely assessment of therapeutic efficacy of the new therapeutic regimens using the imaging technologies will guide the optimization of the delivery systems and treatment protocols to achieve the best possible outcomes and to cure the disease.
The specific aims of this project are 1) to first establish molecular imaging technologies for non-invasive image-guided inhibition of EMT with targeted multifunctional siRNA delivery systems in treating metastatic breast cancer; 2) to evaluate and optimize image-guided silence of EMT-regulatory genes and inhibition of BC EMT and metastasis using targeted multifunctional siRNA delivery systems; 3) to evaluate and optimize image-guided combination therapy of the multifunctional siRNA delivery systems and chemotherapeutics in treating TNBC. Substantial preliminary data have been obtained to demonstrate the effectiveness of the proposed image-guided therapeutic regimens in treating metastatic breast cancer. Our long-term goal is to develop an image-guided therapeutic approach to effectively treat life-threatening metastatic BC.

Public Health Relevance

This project will be focused on developing new image-guided therapeutic strategy by targeting proteins in key biological events associated with metastasis to treat life- threatening metastatic breast cancer. The new therapy has a great potential to prevent breast cancer metastasis and alleviate the resistance of cancer cells to chemotherapy, and to eventually cure the disease. Preclinical and clinical development of a lead therapeutic regimen will be initiated once it is identified and validated in the project.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Tandon, Pushpa
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Case Western Reserve University
Biomedical Engineering
Biomed Engr/Col Engr/Engr Sta
United States
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Qutaish, Mohammed Q; Zhou, Zhuxian; Prabhu, David et al. (2018) Cryo-Imaging and Software Platform for Analysis of Molecular MR Imaging of Micrometastases. Int J Biomed Imaging 2018:9780349
Han, Zheng; Cheng, Han; Parvani, Jenny G et al. (2018) Magnetic resonance molecular imaging of metastatic breast cancer by targeting extradomain-B fibronectin in the tumor microenvironment. Magn Reson Med 79:3135-3143
Lu, Zheng-Rong (2017) Magnetic resonance molecular imaging for non-invasive precision cancer diagnosis. Curr Opin Biomed Eng 3:67-73
Han, Zheng; Lu, Zheng-Rong (2017) Targeting Fibronectin for Cancer Imaging and Therapy. J Mater Chem B 5:639-654
Morrison, Chevaun D; Chang, Jenny C; Keri, Ruth A et al. (2017) Mutant p53 dictates the oncogenic activity of c-Abl in triple-negative breast cancers. Cell Death Dis 8:e2899
Han, Zheng; Wu, Xiaohui; Roelle, Sarah et al. (2017) Targeted gadofullerene for sensitive magnetic resonance imaging and risk-stratification of breast cancer. Nat Commun 8:692
Gujrati, Maneesh; Vaidya, Amita M; Mack, Margaret et al. (2016) Targeted Dual pH-Sensitive Lipid ECO/siRNA Self-Assembly Nanoparticles Facilitate In Vivo Cytosolic sieIF4E Delivery and Overcome Paclitaxel Resistance in Breast Cancer Therapy. Adv Healthc Mater 5:2882-2895
Malamas, Anthony S; Jin, Erlei; Gujrati, Maneesh et al. (2016) Dynamic Contrast Enhanced MRI Assessing the Antiangiogenic Effect of Silencing HIF-1? with Targeted Multifunctional ECO/siRNA Nanoparticles. Mol Pharm 13:2497-506
Morrison, Chevaun D; Allington, Tressa M; Thompson, Cheryl L et al. (2016) c-Abl inhibits breast cancer tumorigenesis through reactivation of p53-mediated p21 expression. Oncotarget 7:72777-72794
Robinson, Nathaniel J; Schiemann, William P (2016) Means to the ends: The role of telomeres and telomere processing machinery in metastasis. Biochim Biophys Acta 1866:320-329

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