# Targeting eEF2 with the protein translation elongation inhibitor SVC112 in head and neck squamous cancer

> **NIH NIH P50** · UNIVERSITY OF COLORADO DENVER · 2022 · $328,151

## Abstract

SUMMARY. Radiation therapy (RT) and immunotherapy with PD-1 inhibitors are used in early and relapsed
head and neck squamous cell cancers (HNSCC), respectively; RT failures are common, and most patients do
not respond to PD-1 inhibition. Both impact the tumor microenvironment (TME), but studying the TME is limited
by the availability of models with human immune cells. PI3K/mTOR signaling regulates protein synthesis through
transcription factors such as Myc or SOX2, that dictate growth, invasion, and drug resistance in HNSCC. SVC112
is a fully synthetic small molecule that inhibits protein synthesis at the elongation step by inhibiting eEF2. SVC112
had greater effect on cancer over non-cancer cells, and was more potent and selective than homoharringtonin
(HHT), an FDA-approved translation elongation inhibitor. Cancer cells had higher eEF2 than non-cancer cells,
and the most susceptible strain had the highest eEF2 expression. SVC112 depleted SOX2, Myc, and Cyclin D1
in HNSCC cells at concentrations that had minimal effect on the rest of the proteome. SVC112 decreased
spheres in vitro, reduced tumor growth in vivo in patient-derived xenografts (PDX), and induced tumor regression
when given with RT in three out of four PDX models. SVC112 also reduced the E6 oncoprotein in human
papillomavirus-driven cells. Lastly, SVC112 decreased PD-1 ligand (PD-L1) resulting in decreased PD-L1:PD-1
interactions leading to increased sphere T cell invasion, while having no effect on T cell fitness or function. Thus,
SVC112 can target multiple key pathways (SOX2, Myc, PD-L1), and can influence the TME to reverse immune
evasion. To test SVC112’s therapeutic potential in HNSCC, several unique tools will be used including 1) spheres
containing cancer cells and T cells (iSpheres) that enable studying TME interactions and immunotherapy in vitro,
2) syngeneic mouse models of HNSCC, and 3) humanized mouse (HM) models, developed by the PI, that enable
studying TME interactions and immunotherapy in vivo. The hypothesis that SVC112’s discriminating effect is
due to selective depletion of key proteins will be tested by ribosome profiling (to identify mRNA targets) and
proteomics analysis (to identify proteins targets). Then, we will test the mechanism of SVC112 synergy with RT,
and if the modulation of the TME by SVC112 will further enhance RT efficacy. Lastly, the hypothesis that
reduction of PD-L1 by SVC112 in HNSCC will alter the tumor-immune interaction will be tested by defining the
effect of SVC112 on the expression of proteins critical for the TME, T cell tumor infiltration, and cancer-immune
crosstalk. The effect of SVC112 on T cell fitness and function will be examined, aiding SVC112 translation. We
will assess SVC112 and PD-1 inhibition in iSphere and HM models, and explore their efficacy when both are
combined. Lastly, we will test the predictive value of eEF2 in SVC112 susceptibility, and we will assess eEF2
expression in human tumors, to enable identifying a compani...

## Key facts

- **NIH application ID:** 10477463
- **Project number:** 5P50CA261605-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Antonio Jimeno
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $328,151
- **Award type:** 5
- **Project period:** 2021-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10477463

## Citation

> US National Institutes of Health, RePORTER application 10477463, Targeting eEF2 with the protein translation elongation inhibitor SVC112 in head and neck squamous cancer (5P50CA261605-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10477463. Licensed CC0.

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