Claudin-low breast cancer (CLBC), characterized by mesenchymal and cancer stem cell-like qualities, is an aggressive subtype with a poor prognosis. Currently, there are no CLBC-specific therapeutic regimens. We are the first to show that silver nanoparticles (AgNPs) possess a desirable combination of selective cytotoxicity and radiation dose enhancement effects for treatment of CLBC at doses that are non-toxic to non-cancerous breast and other cells. No other nanomaterial is known to possess a breast-cancer subtype specific cytotoxic or radiation sensitization profile. Following an extensive screening and characterization process, we now have a lead AgNP formulation that shows in vivo efficacy against CLBC following intravenous injection in tumor bearing mice, which provides evidence that a therapeutic window exists for the safe use of this nanomaterial. The selectivity of AgNPs for CLBC is due in part to a failure of CLBC cells to mitigate DNA and protein damage caused by AgNPs, and is further enhanced by what may be a general vulnerability of mesenchymal cancers like CLBC to endoplasmic reticulum (ER) stress, which we found is selectively induced in CLBC by AgNPs. Our central hypothesis is that AgNPs can be used as a form of precision medicine for the treatment of the claudin-low and other mesenchymal breast cancers. Notably, CLBC cell lines and patient samples express significantly less ESRP1 (endothelial splicing regulatory protein) than other breast cancer subtypes. ESRP1 regulates a transcriptional program necessary for epithelial to mesenchymal transition (EMT). We find that baseline ESRP1 expression inversely correlates with AgNP sensitivity and ESRP1 knockdown increases AgNP sensitivity. Although CLBC represents only 5% of breast cancers, our clinical data set of 1954 patients shows that 13% of all breast cancers are ESRP1low (defined as ? mean ESRP1 mRNA in CLBC). Therefore, AgNP treatment could be of benefit to a broader patient population.
In AIM 1, we will test the hypothesis that our optimized AgNPs are effective for treatment and radiosensitization of CLBC without inducing cytotoxicity or DNA damage in normal breast epithelia. We will image and quantify the uptake, subcellular localization, cytotoxicity, DNA damage and radiosensitizing effects of AgNPs on CLBC and normal breast epithelia grown in 3D cell culture and in murine orthotopic tumor models.
In AIM 2, we will test the hypothesis that specific effects of AgNP exposure on redox sensitive proteins, pathways and organelles contribute to the CLBC-specific mechanism of action of AgNPs. We will use the most advanced reagents and novel proteomic approached to identify oxidative damage induced by AgNP exposure in CLBC and non-CLBC cells.
In AIM 3, we will test the hypothesis that an underlying sensitivity to ER stress in mesenchymal cancer cells is responsible for the specificity of AgNPs for CLBC treatment. We will evaluate the influence of ESRP1 expression on AgNP- induced activation of the unfolded protein response indicative of ER stress. This work could identify new therapeutic strategies for CLBC and pave the way for future clinical trials.

Public Health Relevance

Cancer is the second leading cause of death in the United States. This project will assess the promise of nanotechnology in combating this devastating disease. Completion of this project is expected to lead to more effective treatments for cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA207222-01A1
Application #
9307347
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Kondapaka, Sudhir B
Project Start
2017-04-01
Project End
2022-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Biology
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Peak, Taylor C; Praharaj, Prakash P; Panigrahi, Gati K et al. (2018) Exosomes secreted by placental stem cells selectively inhibit growth of aggressive prostate cancer cells. Biochem Biophys Res Commun 499:1004-1010
Suo, Xubin; Eldridge, Brittany N; Zhang, Han et al. (2018) P-Glycoprotein-Targeted Photothermal Therapy of Drug-Resistant Cancer Cells Using Antibody-Conjugated Carbon Nanotubes. ACS Appl Mater Interfaces 10:33464-33473
Holmila, Reetta J; Vance, Stephen A; Chen, Xiaofei et al. (2018) Mitochondria-targeted Probes for Imaging Protein Sulfenylation. Sci Rep 8:6635
Eldridge, Brittany N; Xing, Fei; Fahrenholtz, Cale D et al. (2017) Evaluation of multiwalled carbon nanotube cytotoxicity in cultures of human brain microvascular endothelial cells grown on plastic or basement membrane. Toxicol In Vitro 41:223-231
Fahrenholtz, Cale D; Swanner, Jessica; Ramirez-Perez, Maria et al. (2017) Heterogeneous Responses of Ovarian Cancer Cells to Silver Nanoparticles as a Single Agent and in Combination with Cisplatin. J Nanomater 2017:
Fahrenholtz, Cale D; Ding, Song; Bernish, Brian W et al. (2016) Design and cellular studies of a carbon nanotube-based delivery system for a hybrid platinum-acridine anticancer agent. J Inorg Biochem 165:170-180