A method of profoundly enhancing some cancer treatments could be right under our noses. A study co-authored by a University of Pittsburgh researcher has shown in an animal model that breathing air with a higher than usual concentration of oxygen can alter certain metabolic pathways to allow chemotherapy and immunotherapy to shrink tumors more effectively.
The blood supply of a tumor often does not match the pace of the cancer’s growth, which leads to areas that are ischemic, or oxygen deprived, explained Edwin Jackson, Ph.D., professor of pharmacology and chemical biology, Pitt School of Medicine, and a co-author of a paper published online in Science Translational Medicine. That causes the tumor cells to make adenosine, a molecule that not only promotes blood flow, but also binds to a receptor on killer T-cells and essentially puts them to sleep. In effect, adenosine acts as a shield against immune system cells that would otherwise attack the cancer.
“We realized if we could find a way to block the increase in adenosine, we might be able to help the immune system respond to the tumor to make anti-cancer therapies more effective,” Dr. Jackson said. “This study shows that simply breathing more oxygen can accomplish that aim, which could lead to an amazing breakthrough in cancer treatment.”
The study team, led by Michail Sitkovsky, Ph.D., director of the New England Inflammation and Tissue Protection Institute at Northeastern University, exposed mice with lung tumors to respiratory hyperoxia at levels of 40 to 60 percent oxygen, comparable to what patients might receive in the hospital. Another group of mice breathed air, which is approximately 21 percent oxygen. Tumors in mice that received supplemental oxygen shrank – some regressed completely – and the animals were more likely to survive than those on room air.
“Supplemental oxygen prevented the tumor from making extra adenosine, so the immune cells could do their job and attack the cancer cells,” Dr. Sitkovsky explained. “But if anti-tumor immune cells aren’t present, oxygen has no effect. We hope we will soon see clinical trials of respiratory hyperoxia in combination with immunotherapies to see whether it can help cancer patients.”
He noted also the effects might be stronger in combination with an agent that he calls “super-caffeine,” which blocks the receptor where adenosine binds to inhibit the immune cells.
For Dr. Jackson, whose lab is thought to be the world’s best in the measurement of adenosine and its metabolites, the breakthrough research is personally deeply rewarding. Fourteen years ago, his older brother, James F. Jackson, died at 57 of renal cell carcinoma. In 1986, Mr. Jackson received the National Science Foundation Presidential Award for Excellence in Science Teaching from Vice President George H.W. Bush.
“Jim was my childhood mentor and the reason I am a scientist today. His three years of treatment was an emotional and frustrating time for me because we didn’t have the right tools to help him,” Dr. Jackson said. “I started doing cancer research because of that experience, and I hope these results will one day prevent suffering and loss by countless other families.”
Other study investigators included researchers from the Dana Farber Cancer Institute, Harvard Medical School and the University of Miami. The project was funded by National Institutes of Health grants CA 112561, CA 111985, AT 002788, and AI 091693; National Cancer Institute grant 5PO1CA109094-03; and Northeastern University.
Immunological mechanisms of the antitumor effects of supplemental oxygenation, Stephen M. Hatfield, Jorgen Kjaergaard, Dmitriy Lukashev, Taylor H. Schreiber, Bryan Belikoff, Robert Abbott, Shalini Sethumadhavan, Phaethon Philbrook, Kami Ko, Ryan Cannici, Molly Thayer, Scott Rodig, Jeffrey L. Kutok, Edwin K. Jackson, Barry Karger5 Eckhard R. Podack, Akio Ohta1 and Michail V. Sitkovsky, Science Translational Medicine, DOI: 10.1126/scitranslmed.aaa1260, published 4 March 2015.