# Development of a novel therapeutic agent that exploits specific vulnerabilities in claudin low breast cancer

> **NIH NIH R01** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2021 · $351,544

## Abstract

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 activa...

## Key facts

- **NIH application ID:** 10122915
- **Project number:** 5R01CA207222-05
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Ravi N Singh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $351,544
- **Award type:** 5
- **Project period:** 2017-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10122915

## Citation

> US National Institutes of Health, RePORTER application 10122915, Development of a novel therapeutic agent that exploits specific vulnerabilities in claudin low breast cancer (5R01CA207222-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10122915. Licensed CC0.

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