# Overcoming Hypoxic Resistance in Non-Small Cell Lung Cancer By Targeting Mitochondrial Metabolism

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2021 · $650,406

## Abstract

PROJECT SUMMARY
Many groups are investigating why some lung cancer patients respond well to radio- and immuno-therapies and
some do not. One variable is tumor hypoxia, and many groups have shown it can significantly inhibit the
effectiveness to these therapeutic modalities. Clinical studies have identified hypoxia as an independent
prognostic indicator of poor patient outcomes, but even though this connection has been known for decades, no
FDA-approved intervention exists to clinically overcome hypoxia. Some investigators have tried to deliver more
oxygen to the tumor, but this approach remains constrained due to the poorly formed tumor vasculature. We
have taken an innovative approach and asked if we can reduce demand for, rather than increase supply of,
oxygen to reduce hypoxia. We have found that the FDA-approved vasorelaxant papaverine (PPV) has an off-
target ability to inhibit mitochondrial complex 1, and reduce oxygen consumption rapidly, in low micromolar
concentrations in every cell line tested in vitro. We have also shown that PPV can enhance the effectiveness of
radiation and immune checkpoint blockade (ICB) in preclinical models of lung and other cancers, without
sensitizing well-oxygenated normal tissue. Reducing hypoxia reverses immune privilege, decreases terminally-
exhausted T cells, and increases progenitors that are responsive to PD-1 blockade. We have more recently
developed new derivatives of PPV that have lost their vasorelaxant capability and increased their duration of
action so that they can be improved immuno-sensitizers. We now propose to test the hypothesis that PPV can
effectively enhance the radio- and immuno-therapeutic treatment of preclinical models of lung cancer, and that
it is feasible to add PPV to standard of care therapy for advanced non-small cell lung cancer (NSCLC). We have
examined TCGA databases and found that lung cancer driver mutations in the KEAP1/NRF2 pathway lead to
high levels of mitochondrial gene expression that can cause elevated oxygen metabolism contributing to hypoxia.
In Aim 1, we will investigate the effects of oncogenic NRF2 activation human and murine cells and model tumors
to determine the dependence of these cells on mitochondrial function, how increased oxygen metabolism
contributes to tumor hypoxia, and if therapy-refractory tumors are sensitized by PPV or its derivatives. In Aim 2,
we will examine the effect of tumor hypoxia on the migration and activation of T-cells in model tumors and how
the immune infiltrate changes after reduction of hypoxia with PPV or its derivatives. Finally, in Aim 3 we will
perform a phase 1 clinical trial to determine if the addition of PPV is feasible for patients receiving standard of
care chemoradiation followed by immunotherapy for advanced NSCLC. We will look for effectiveness in changing
tumor oxygenation using paired blood level oxygen determination (BOLD) MRIs, and for changes in immune
populations of peripheral blood mononuclear cells. These stu...

## Key facts

- **NIH application ID:** 10275968
- **Project number:** 1R01CA262388-01
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Nicholas C. Denko
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $650,406
- **Award type:** 1
- **Project period:** 2021-09-22 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10275968

## Citation

> US National Institutes of Health, RePORTER application 10275968, Overcoming Hypoxic Resistance in Non-Small Cell Lung Cancer By Targeting Mitochondrial Metabolism (1R01CA262388-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10275968. Licensed CC0.

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