Of the 1 million cases of newly diagnosed breast cancer worldwide each year, over 170,000 cases are a distinct type of triple-negative breast cancer (TNBC). TNBC lacks expression of estrogen (ER), progesterone (PR) and Her-2/neu. It is not a candidate for two common therapies for breast cancer: hormonal (tamoxifen) and Her-2 targeted (Herceptin) therapy. TNBC is usually found at the late stage and has a higher likelihood of local and distant recurrence and a poor prognosis. The goal of this study is to develop a complete therapeutic approach that merges targeted preoperative adjuvant therapy and image-guided treatment and surgery for preventing local recurrence and distant metastasis. Our team has developed a multifunctional nanoparticle platform that carries therapeutic agents, targets tumor cells and stromal tissues, and produces optical and MR imaging signals. We demonstrated the ability of targeted tumor imaging, tumor growth inhibition, and anti- angiogenesis effects in TNBC animal models. In the proposed study, we will develop receptor-targeted and near infrared dye labeled-magnetic iron oxide nanoparticles (IONPs). These nanoparticles will carry DNA damaging drugs without or with a poly ADP ribose polymerase (PARP) inhibitor for treatment of TNBC, MRI monitoring of drug delivery and response, and optical image-guided surgery. We hypothesize that targeted delivery of high concentrations of the combined therapeutic agents using theranostic nanoparticles and timely assessment of drug delivery and response to the treatment could lead to enhanced therapeutic effects in drug resistant tumor cells, while minimizing systemic toxicity. Image-guided surgery following the targeted therapy allows removal of small drug-resistant residual tumor lesions, which could prevent the development of local recurrence and distant metastasis. First, urokinase plasminogen activator receptor (uPAR) and epidermal growth factor receptor (EGFR) will be validated as molecular targets for targeted therapeutics using two large cohorts (>3000 cases) of breast cancer tissues (Aim 1). We will produce a new generation of theranostic nanoparticles with enhanced drug delivery into the tumor by avoiding macrophage uptake and increasing in drug loading and release. We will determine biodistribution, and the effects of targeted therapy, MRI-guided drug delivery and evaluating response in TNBC animal models using different theranostic IONPs to select the lead theranostic IONPs for further preclinical studies (Aim 2). We will use the mice bearing orthotopic TNBC to study the effects of integration of preoperative targeted neoadjuvant therapy, monitoring therapeutic responses by non-invasive MRI, and intraoperative optical imaging of tumor lesions after administration of the theranostic IONPs on the incidences of local and distant recurrence as well as overall survival of the mice (Aim 3). We will examine systemic toxicity, and pharmacokinetics/pharmacodynamics of the selected lead theranostic IONPs in normal and tumor bearing mice (Aim 4). Clinical impact: The proposed study addresses the urgent need in clinical management of TNBC to improve the survival of patients afflicted with TNBC.

Public Health Relevance

The objective of this research project is to develop an integrated targeted therapy and image-guided treatment clinical protocol using theranostic nanoparticles and novel tumor imaging approaches for effective treatment of triple negative breast cancer (TNBC). We plan to use receptor-targeted magnetic iron oxide nanoparticles that carry chemotherapy drugs and an optical imaging agent for targeted neoadjuvant therapy, monitoring therapeutic response by non-invasive MRI, and intraoperative identification and removal of residual drug resistant tumors using a new SpectroPen optical imaging device. The proposed study will develop the first targeted theranostic agent and clinical protocol for the treatment of this aggressive type of breast cancer and for improving survival of the TNBC patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA154129-04
Application #
8712191
Study Section
Special Emphasis Panel (ZRG1-OTC-K (04))
Program Officer
Fu, Yali
Project Start
2011-09-16
Project End
2016-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
4
Fiscal Year
2014
Total Cost
$312,222
Indirect Cost
$107,019
Name
Emory University
Department
Surgery
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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Zhou, Hongyu; Qian, Weiping; Uckun, Fatih M et al. (2015) IGF1 Receptor Targeted Theranostic Nanoparticles for Targeted and Image-Guided Therapy of Pancreatic Cancer. ACS Nano 9:7976-91
Yang, Emmy; Qian, Weiping; Cao, Zehong et al. (2015) Theranostic nanoparticles carrying doxorubicin attenuate targeting ligand specific antibody responses following systemic delivery. Theranostics 5:43-61
Satpathy, Minati; Wang, Liya; Zielinski, Rafal et al. (2014) Active targeting using HER-2-affibody-conjugated nanoparticles enabled sensitive and specific imaging of orthotopic HER-2 positive ovarian tumors. Small 10:544-55
Xi, Lei; Satpathy, Minati; Zhao, Qing et al. (2014) HER-2/neu targeted delivery of a nanoprobe enables dual photoacoustic and fluorescence tomography of ovarian cancer. Nanomedicine 10:669-77
Xi, Lei; Grobmyer, Stephen R; Zhou, Guangyin et al. (2014) Molecular photoacoustic tomography of breast cancer using receptor targeted magnetic iron oxide nanoparticles as contrast agents. J Biophotonics 7:401-9

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