# Targeting SHP2 as a precision medicine for the treatment of HER2-positive breast cancer

> **NIH NIH R01** · WEST VIRGINIA UNIVERSITY · 2020 · $343,125

## Abstract

PROJECT SUMMARY
Approximately 20% of breast cancer (BC) is caused by overexpression of the human epidermal growth
factor receptor 2 (HER2), on the basis of which anti-HER2 therapies have been developed. Although these
drugs have benefited BC patients, development of resistance and disease recurrence continue to be the
major clinical challenges. These clinical problems warrant studies on alternative therapeutic strategies to
treat HER2-positive BC. In this application, we propose to develop a new targeted therapy through
pharmacological inhibition of the Src homology phosphotyrosyl phosphatase 2 (SHP2), which acts by
blocking HER2 and switch oncogene overexpression. As opposed to the existing anti-HER2 drugs that act
by inactivating the already expressed protein, targeting SHP2 has the potential to block the process of
overexpression. We predict that targeting SHP2 that controls multiple signaling pathways is more effective
and at the same time eliminates the need for developing drugs against multiple targets. In addition, targeting
SHP2 can reduce toxicities associated with the use of drug cocktails and enormously cuts the cost of
treatment. In line with this concept, we have invented a specific small molecule SHP2 inhibitor (WGMDY)
that shows promising anti-cancer effects in naïve and anti-HER2 drug resistant cells in culture and in vivo.
In this study, we will investigate the potential of SHP2 as a drug target and WGMDY as an anti-cancer
agent. The overall hypothesis is that pharmacological targeting of SHP2 induces remission of both
treatment-naïve and anti-HER2 drug resistant cells and tumors. To attain these goals, three specific
aims have been proposed. First (Specific aim #1), we will determine the effect of pharmacological targeting
of SHP2 on oncogene expression, cell proliferation, transformation, and cancer stem cell properties.
Second (Specific aim #2), we will determine maximum tolerable dose, toxicity, bioavailability, and stability
of WGMDY in vivo. And third (Specific aim #3), we will determine the anti-cancer activity of SHP2 targeting
with WGMDY in primary spontaneous and xenograft models and in brain metastatic models. The outcome
of the proposed study can show the potential of SHP2 as a drug target and the viability of the anti-SHP2
compound as a lead molecule for future development of anti-SHP2 drugs.

## Key facts

- **NIH application ID:** 9852423
- **Project number:** 5R01CA213996-03
- **Recipient organization:** WEST VIRGINIA UNIVERSITY
- **Principal Investigator:** Yehenew M Agazie
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $343,125
- **Award type:** 5
- **Project period:** 2018-03-05 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852423

## Citation

> US National Institutes of Health, RePORTER application 9852423, Targeting SHP2 as a precision medicine for the treatment of HER2-positive breast cancer (5R01CA213996-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9852423. Licensed CC0.

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