# Project 3:  Targeting Head and Neck Cancer with Synstatin Therapeutics

> **NIH NIH P50** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $247,093

## Abstract

PROJECT SUMMARY
Head & Neck cancer (HNC) is the sixth most prevalent cancer worldwide, with over 600,000 new diagnoses
annually. Long-term survival rates for HNC have remained relatively unchanged for the past several decades.
Thus, the identification of new targets and therapeutic approaches in HNC are desperately needed. This
proposal identifies two new molecular targets in HNC and a new class of inhibitors that show significant
promise as new therapies. The molecular targets are signaling complexes organized by syndecans, a family of
matrix receptors; they are comprised of integrins, and receptor tyrosine kinases, specifically the epidermal
growth factor receptor (EGFR) and insulin-like growth factor-1 receptor (IGF1R). These two kinases are
overexpressed in HNC and are known to be causal factors. The integrins that are captured (the αvβ3/αvβ5
integrin with IGF1R and the α6β4 integrin with EGFR) are also known to be causal in HNC, suggesting that the
IGF1R- and EGFR-coupled signaling complexes are likely to have central roles in this disease. Competitive
peptides (called synstatins or SSTNs) represent a new class of inhibitors that mimic motifs in the extracellular
domains of the syndecans and thus block the assembly and signaling of these complexes. Preliminary findings
show that the SSTNs block the survival of HNC cells, as well as endothelial cells activated by the tumors to
undergo angiogenesis. SSTNs have no effect on normal, resting cells, have no apparent toxicity in animals and
are remarkably stable in human plasma and in vivo. We propose to test the hypothesis that these novel
synstatins shrink or eradicate HN tumors by targeting the tumor cells as well as the angiogenesis upon which
they depend. Specifically, we plan to: (1) Characterize the mechanism of SSTN inhibition of syndecan-coupled
EGFR and IGF1R in HNC tumor cells; (2) Evaluate SSTN efficacy in vivo during the progression of HNC from
precancerous lesions to tumor formation using the 4-NQO mouse model; and (3) Analyze biomarkers
predictive of syndecan-coupled EGFR and IGF1R activity in human tumors and patient-derived HNC
xenografts undergoing SSTN therapy. Our goal will be to validate biomarkers that can be used to identify HNC
patients that are candidates for SSTN therapy and to demonstrate that SSTNs show significant promise as
novel therapeutics for HNC when compared to inhibitors currently in clinical use.

## Key facts

- **NIH application ID:** 9988232
- **Project number:** 5P50DE026787-05
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** ALAN C RAPRAEGER
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $247,093
- **Award type:** 5
- **Project period:** 2016-08-02 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9988232

## Citation

> US National Institutes of Health, RePORTER application 9988232, Project 3:  Targeting Head and Neck Cancer with Synstatin Therapeutics (5P50DE026787-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9988232. Licensed CC0.

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