Nicholas C. Denko
Ohio State University, OH·Medicine & Clinical Research
Some lung cancer patients respond well to radiation and immunotherapy, while others do not. One major reason is tumor hypoxia, meaning low oxygen inside the tumor.
- Fields
Medicine & Clinical Research
Pharmacology
Microbiology & Immunology
- Topics
non-small cell lung cancer
tumor hypoxia
papaverine
- Grants
- 1 known grant, through Aug 2027
What they work on
- Determine whether oncogenic NRF2 activation, which can follow KEAP1 mutations, makes lung cancer cells and model tumors dependent on mitochondria and more hypoxic, and whether papaverine or its derivatives sensitize these therapy-resistant tumors.
- Examine how tumor hypoxia affects T-cell migration and activation in model tumors, and how immune infiltrates change after papaverine reduces oxygen consumption.
- Conduct a phase 1 clinical trial testing whether papaverine can feasibly be added to chemoradiation and immunotherapy for advanced NSCLC, measuring tumor oxygenation with BOLD MRI and immune changes in blood cells.
More about the research
Hypoxia weakens both treatments and predicts poorer outcomes, yet no FDA-approved way to overcome it exists. Delivering more oxygen has been hard because tumor blood vessels are poorly formed. Instead, this project tries to lower the tumor's demand for oxygen. The team found that papaverine (PPV) can do this. PPV is an FDA-approved drug that relaxes blood vessels. It also blocks mitochondrial complex 1, a key part of the cell's energy-producing machinery, and so quickly cuts oxygen use. In earlier preclinical models of lung and other cancers, the team showed that PPV boosted radiation and immune checkpoint blockade, a therapy that releases brakes on immune cells, without sensitizing well-oxygenated normal tissue. Reducing hypoxia also lowered the number of exhausted T cells and raised the number of progenitor T cells that respond to PD-1 blockade. The team has also made PPV derivatives that no longer relax blood vessels and last longer in the body.
Why it matters
Tumor hypoxia makes radiation and immunotherapy less effective for many lung cancer patients, and no approved treatment addresses it. Repurposing papaverine, an existing FDA-approved drug, or its new derivatives could improve responses to standard therapy for people with advanced non-small cell lung cancer. The phase 1 trial will show whether adding the drug is feasible and will guide future clinical trials.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
David Tweardy
University of Texas MD Anderson Cancer Center, TX·Medicine & Clinical Research
Determine whether the STAT3 inhibitor TTI-101, alone or combined with anti-PD-1 antibody, treats lung tumors effectively in the K-ras mutant CC-LR mouse model of non-small cell lung cancer.
Jun Wang
New York University, NY·Microbiology & Immunology
Determine whether Siglec-15, a tumor-associated immune brake, also suppresses myeloid cells such as macrophages, and identify the receptors it binds on myeloid cells and T cells.
David Shackelford
University of California-Los Angeles, CA·Medicine & Clinical Research
Dissect mitochondrial energy production in therapy-resistant lung adenocarcinomas in living models, using 18F-BnTP PET imaging, a scan that reads out mitochondrial membrane potential.
The school
Ohio State University: 71 labs on PI Pages, $1.6B a year on research, 882 research doctorates a year.
Reach out
A start for your email. Fill in the brackets.