# Targeting NRF2 in Head and Neck Squamous Cell Carcinoma

> **NIH VA IK2** · ST. LOUIS VA MEDICAL CENTER · 2024 · —

## Abstract

Recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) is a devastating
diagnosis and is largely incurable even with maximal therapy. Despite the recent FDA approval
of immunotherapy drugs targeting the PD-1/PDL-1 axis, response rates in HNSCC patients are
less than 20% with durable responses in less than 5% of patients. Therefore, there is a pressing
need for novel treatment modalities that target tumor cell defenses and work synergistically with
existing treatment modalities to improve patient outcomes.
Analyses of large genomic libraries have highlighted that dysregulation of the NRF2 oxidative
stress pathway occurs in up to 40% of HNSCC tumors indicating a central role of this pathway
in HNSCC tumorigenesis. This pathway is responsible for maintaining cellular reduction-
oxidation balance and preventing toxin/carcinogen/inflammation induced cellular damage. In
cancer cells, constitutive activation of this pathway induces activation of over 200 antioxidant-
response element (ARE)- related cytoprotective genes that support rapid cell growth and
proliferation in hypoxic, nutrient-depleted environments. NRF2 activation confers a survival
advantage to tumor cells and is associated with immune evasion, treatment resistance, and
worse clinical outcomes. However, no preclinical models of NRF2-active head and neck cancer
exist and, therefore, mechanistic studies to understand this clinical phenotype are lacking.
Our lab conducted a chemical screen of over 35,000 FDA-approved drugs to identify inhibitors
of the NRF2 pathway. We discovered that the antiplasmodial drug, pyrimethamine(PYR),
effectively inhibited NRF2 pathway activation including downstream effector proteins through its
inhibition of DHFR. We are also investigating two DHFR inhibitors, methotrexate and a novel
PYR analog, WCDD115, which are highly potent inhibitors of NRF2 activity. Neither drug has
been studied in selective NRF2-active tumors previously.
The objectives of this study are to 1) Characterize the downstream effects of constitutive NRF2
activation on ARE gene activation, tumor growth, and immune cell infiltration and 2) Evaluate
the anti-tumor activity of pyrimethamine and methotrexate on the NRF2 pathway and as a
sensitizer to anti-PD1 checkpoint blockade.
We will utilize engineered mouse head and neck cancer models to characterize the molecular
and biologic phenotype associated with NRF2 pathway activation. We will perform targeted
proteomics, transcriptomics and flow cytometry to interrogate the immune microenvironment
and NRF2 pathway activity. We will then evaluate if DHFR inhibition reverses this NRF2-
mediated biology and induces a more favorable microenvironment to support anti-PD1
inhibition. If successful, we anticipate that this novel treatment approach would lend itself well to
an early phase clinical trial. Given the prevalence of head and neck cancer, especially in the VA
Health Care System, and the poor response rates to immunotherapy currently, ...

## Key facts

- **NIH application ID:** 10701532
- **Project number:** 1IK2BX006120-01A1
- **Recipient organization:** ST. LOUIS VA MEDICAL CENTER
- **Principal Investigator:** Paul Zolkind
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2023-10-01 → 2027-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10701532

## Citation

> US National Institutes of Health, RePORTER application 10701532, Targeting NRF2 in Head and Neck Squamous Cell Carcinoma (1IK2BX006120-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10701532. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*