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Pyrimethamine as an Inhibitor of NRF2 in HPV-unrelated Locally Advanced Head and Neck Squamous Cell Carcinoma

Head and Neck Cancer Clinical Trial

Official title:
Early Phase I Window of Opportunity Biomarker and Safety Trial to Test Pyrimethamine as an Inhibitor of NRF2 in HPV-unrelated, Locally Advanced Head and Neck Squamous Cell Carcinoma

Clinical Trial Summary

NRF2 activation, observed in up to 40% of head and neck squamous cell carcinoma (HNSCC) tumors, plays a critical role in tumor progression, metastasis, and radiation therapy resistance. The investigators have recently discovered that pyrimethamine (PYR) and its analogs have an inhibitory effect on NRF2 activity in vitro and in mouse models via inhibition of dihydrofolate reductase (DHFR). Pyrimethamine is an established drug that has been used for decades for treatment of protozoan infections and malaria. A growing body of research shows that it has potential antitumor activity, however its activity on growing human tumors has not been previously studied. The primary efficacy goal of this study is to evaluate the activity of pyrimethamine on human tumors as demonstrated by inhibition of DHFR and downregulation of NRF2 pathway activity. On-target inhibition of DHFR by pyrimethamine results in the stabilization and increased protein expression of human DHFR. The primary efficacy hypothesis of this study is that treatment with pyrimethamine will result in a 50% increase in DHFR protein within the tumor cells as measured by quantitative western blot analysis. Secondarily, among those tumors classified as NRF2-active on pre-treatment biopsy, the investigators hypothesize there will be a 50% reduction in NRF2 activity as measured by SureQuant targeted proteomic analysis.

Clinical Trial Description

n/a

Study Design

Related Conditions & MeSH terms

Clinical Trial Details
NCT number NCT05678348
Study type Interventional
Source Washington University School of Medicine
Contact Paul Zolkind, M.D.
Phone 314-362-7395
Email pzolkind@wustl.edu
Status Recruiting
Phase Early Phase 1
Start date August 3, 2023
Completion date April 15, 2026
View Details
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