Breast cancer is a major global health issue; it is the second most common form of cancer in women exceeded only by lung cancer. Current breast cancer treatments are regulated by cell surface presentation; for example, breast cancer cells that express estrogen receptor-? (ER?) and human epidermal growth receptor-2 (HER2) on their surface are treated with hormone (anti-estrogen or aromatase inhibitors) or targeted (Herceptin) therapies, respectively. In this proposal, we propose a personalized approach to treat four metastatic breast cancer populations: black, white, over 40 and under 40. These populations were chosen based on statistical differences in survival and rate of diagnoses. I will characterize the surface density and proximity of two Gprotein coupled receptors that facilitate tumor chemotaxis, CXC chemokine receptor type 4 (CXCR4) and CC chemokine receptor type 7 (CCR7). CXCR4 and CCR7 induce directional migration of tumor cells along chemokine gradients in a manner similar to lymphocyte homing. In addition, lipocalin-2 (Lcn2) has been shown to induce the epithelial to mesenchymal transition (EMT). I propose to synthesize complementary engineered liposomes (CELs) that cooperatively bind CXCR4 and CCR7 and deliver short interfering RNA (siRNA) to knockdown Lcn2. Homogeneous and biphasic CELs are designed to complement the relative surface density and organization of receptors on breast cancer cells by allowing conjugated antibodies to rearrange on the surface or clustering antibodies within gel-phase lipid domains. CEL therapies will be designed to enhance cooperative binding to each cell type and be evaluated to reduce cell migration and invasion. Mechanistic studies will complement in vitro studies; the expression of RhoA, Rac1, Erk1, PI3K, E-cadherin, vimentin, and fibronectin will assess the effect of CEL therapy on cell migration, activation, survival, and the EMT. In vivo tumor progression and metastasis will be evaluated after delivery of CEL therapies. This work will demonstrate similarities and differences between 6 different breast cancer cell lines and deliver a platform technology designed specifically to address tumor metastasis. In comparison to the antibody and the antagonist targeted towards CXCR4 in clinical trials, this method has the advantage of localizing within tumors, cooperatively binding multiple chemokine receptors, blocking chemotaxis, delivering Lcn2 siRNA to impede the EMT, and monitoring biodistribution in vivo via the incorporation of a near infrared chromophore. My previous work, targeting cytokine-activated endothelial cells, presents compounding evidence that vehicles that complement the cell surface enhance binding. I propose to use our knowledge and experience in chemical engineering, material science, and nanotechnology to develop therapeutics that will increase breast cancer patient survival by inhibiting tumor progression and metastasis.

Public Health Relevance

Breast cancer is the second most common form of cancer in women exceeded only by lung cancer. This proposal will develop personalized therapeutics that target metastatic breast cancer cells and mechanisms that govern metastasis. I will characterize breast cancer cell lines from white, black, under 40, and over 40 populations and synthesize vehicles specifically designed to complement the relative molecular density and organization of receptors on these breast cancer cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
NIH Director’s New Innovator Awards (DP2)
Project #
4DP2CA174495-03
Application #
9540125
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Woodhouse, Elizabeth
Project Start
2012-09-20
Project End
2019-01-31
Budget Start
2017-07-01
Budget End
2019-01-31
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Northeastern University
Department
Engineering (All Types)
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
001423631
City
Boston
State
MA
Country
United States
Zip Code
02115
Guo, Peng; Liu, Daxing; Subramanyam, Kriti et al. (2018) Nanoparticle elasticity directs tumor uptake. Nat Commun 9:130
Tao, Yu; Li, Mingqiang; Auguste, Debra T (2017) Pattern-based sensing of triple negative breast cancer cells with dual-ligand cofunctionalized gold nanoclusters. Biomaterials 116:21-33
Tao, Yu; Li, Mingqiang; Kim, Bumjun et al. (2017) Incorporating gold nanoclusters and target-directed liposomes as a synergistic amplified colorimetric sensor for HER2-positive breast cancer cell detection. Theranostics 7:899-911
Guo, Peng; Yang, Jiang; Bielenberg, Diane R et al. (2017) A quantitative method for screening and identifying molecular targets for nanomedicine. J Control Release 263:57-67
Guo, Peng; Yang, Jiang; Jia, Di et al. (2016) ICAM-1-Targeted, Lcn2 siRNA-Encapsulating Liposomes are Potent Anti-angiogenic Agents for Triple Negative Breast Cancer. Theranostics 6:1-13
Tao, Yu; Auguste, Debra T (2016) Array-based identification of triple-negative breast cancer cells using fluorescent nanodot-graphene oxide complexes. Biosens Bioelectron 81:431-437
Veneti, Eleftheria; Tu, Raymond S; Auguste, Debra T (2016) RGD-Targeted Liposome Binding and Uptake on Breast Cancer Cells Is Dependent on Elastin Linker Secondary Structure. Bioconjug Chem 27:1813-21
Wang, Biran; Guo, Peng; Auguste, Debra T (2015) Mapping the CXCR4 receptor on breast cancer cells. Biomaterials 57:161-8
Liu, Daxing; Auguste, Debra T (2015) Cancer targeted therapeutics: From molecules to drug delivery vehicles. J Control Release 219:632-643
Guo, Peng; Huang, Jing; Wang, Liya et al. (2014) ICAM-1 as a molecular target for triple negative breast cancer. Proc Natl Acad Sci U S A 111:14710-5

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