# GSTP1-induced S-glutathionylation in lung cancer

> **NIH NIH R01** · UNIVERSITY OF VERMONT & ST AGRIC COLLEGE · 2020 · $356,850

## Abstract

PROJECT SUMMARY
Lung cancer is the most lethal of any of the common cancers. Targeted therapy has a demonstrated benefit
in the treatment of lung cancer so identifying novel druggable pathways is a priority. Glutathione S-
transferase P1 (GSTP1) is an enzyme that catalyzes the post-translational modification, protein S-
glutathionylation. Our preliminary data indicate that 1) GSTP1 over-expression and increased protein S-
glutathionylation occurs in approximately 40% of human resected lung adenocarcinomas and is associated
with a worse prognosis for early lung cancers; 2) GSTP1-induced S-glutathionylation is important for
glycolysis and tumorigenesis in our models of lung adenocarcinoma, and pharmacological GSTP1 inhibition
results in decreased tumor formation; and 3) GSTP1-induced S-glutathionylation controls pyruvate kinase
M2 (PKM2) conformation. GSTP1 expression is strongly associated with a worse prognosis with a potential
ability to identify high-risk individuals who may benefit from targeted treatment strategies. TLK199 is an
orally available agent and has an excellent safety profile in Phase II trials (for hematologic cancers). This
proposal will focus on addressing the mechanisms of GSTP1-induced S-glutathionylation and its role in
tumorigenesis and evaluating the potential for GSTP1 targeted therapies. The hypothesis: S-
glutathionylation (notably of PKM2) driven by GSTP1 is important in increasing glycolysis during lung
tumorigenesis. Ways to attenuate or reverse S-glutathionylation are thus anticipated to decrease glycolysis
and to disrupt tumor cell growth and will be tested in 3 specific aims. In Aim 1 we will determine the impact
of inhibition of S-glutathionylation or its reversal on KRASG12D-induced tumorigenesis in an inducible lung
cancer mouse model and evaluate the effect of TLK199 on tumor development and growth. This system
will also allow us to identify further downstream metabolic effects and targets of GSTP1-induced protein S-
glutathionylation. Aim 2 will address the importance of pyruvate kinase M2 in KRASG12D-induced
tumorigenesis and investigate the impact of GSTP-linked PKM2 glutathionylation. The goal of Aim 3 is to
evaluate GSTP1, overall S-glutathionylation and PKM2 in adenocarcinoma and in primary
adenocarcinoma-generated patient-derived tumor xenograft (PDX) mice. We will establish PDX mice from
lung cancer biopsies from our actively enrolling lung cancer study at the University of Vermont and the
effects of pharmacological inhibition of GSTP on primary tumor cell and PDX mice will be evaluated.
Completion of the Aims of this proposed work may prove foundational for clinical investigation of the
GSTP1 inhibitor TLK199 for treatment of lung cancer.

## Key facts

- **NIH application ID:** 9922235
- **Project number:** 5R01CA219156-04
- **Recipient organization:** UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
- **Principal Investigator:** Adrianus (Jos)L.J. Van der Velden
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $356,850
- **Award type:** 5
- **Project period:** 2017-06-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9922235

## Citation

> US National Institutes of Health, RePORTER application 9922235, GSTP1-induced S-glutathionylation in lung cancer (5R01CA219156-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9922235. Licensed CC0.

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