# Targeted Inhibition in Triple Negative Breast Cancer

> **NIH NIH R21** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $207,495

## Abstract

ABSTRACT
We have identified a small molecule lead that at low doses decreases the proliferation of triple negative
breast cancer (TNBC) cells while sparing normal epithelial cells. Mechanistically, our lead targets the
phosphatase activity of Sts-1, a novel target that is overexpressed in TNBC and whose high expression
confers poor overall survival in ER-(-) but not in ER-(+) patients. Our preliminary data show that
inhibiting Sts-1 is a potent mechanism of treatment, as tumors induced by HCC1937 cell xenografts in
mice carrying a Sts-1 targeting shRNA grew significantly smaller than tumors from control cells with
non-targeting shRNA. In cell culture, decreasing Sts-1 expression decreased proliferation of TNBC but
not of control cells. Given these activities, the goal of this research proposal is to validate the
mechanism of action and to test the efficacy of our lead in an in vivo xenograft mouse model of TNBC.
We will focus on TNBC because it is among the most aggressive of breast cancer subtype, with a high
propensity for metastasis, poor prognosis, and short time to relapse and death. TNBC represents a
clinical challenge because it does not benefit from hormonal therapies or other targeted treatments.
Chemotherapy, with its adverse side effects, remains the cornerstone for TNBC treatment and chemo-
agents are often administered individually or in combination; surgery and radiation are also commonly
used. Our long-term goal is to develop small molecule inhibitors of the phosphatase activity of Sts-1
into a novel TNBC therapy.
Our working hypothesis is that small molecule inhibitors of Sts-1 will restore c-Cbl's ability to degrade
its targets (e.g. EGFR, c-Met) by ubiquitination - thereby inhibiting TNBC growth. To validate the
mechanism of action of H9 and determine its potency in vivo, Aim 1 will test the effect of H9 on the
activity of the c-Cbl/EGFR, c-Cbl/c-Met, and mTOR/S6K axes under acute and chronic growth
conditions, investigate the cellular pathways modulated by compound H9 and compare them to Sts-1
silencing using unbiased approaches, and examine and validate binding of H9 to Sts-1 phosphatase
domain using structural and biophysical techniques and site-directed mutagenesis. Aim 2 will test the
ability of compound H9 to inhibit growth of TNBC tumors in vivo. We will Initiate toxicity and
pharmacokinetic studies to determine compound stability and optimal dosage to achieve functional
serum concentrations of compound H9 and test the ability of H9 to inhibit growth of TNBC xenograft
tumors in vivo.

## Key facts

- **NIH application ID:** 9750252
- **Project number:** 5R21CA229930-02
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Nicolas Nassar
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $207,495
- **Award type:** 5
- **Project period:** 2018-07-24 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9750252

## Citation

> US National Institutes of Health, RePORTER application 9750252, Targeted Inhibition in Triple Negative Breast Cancer (5R21CA229930-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9750252. Licensed CC0.

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