Important new findings about how to test cancer-fighting drugs

Researchers from Indiana University School of Medicine are discovering new ways to find out how effective a drug might be against cancer. Their findings are detailed in a new paper published by Science Advances.

"This paper completely changes the way we need to collect tumor tissues and test for drug sensitivity," said Harikrishna Nakshatri, Ph.D., a senior author of the paper. Nakshatri is the Marian J. Morrison professor of breast cancer research at IU School of Medicine and a researcher with the Vera Bradley Foundation Center for Breast Cancer Research at the Indiana University Melvin and Bren Simon Comprehensive Cancer Center. Hal Broxmeyer, Ph.D., a distinguished professor at IU School of Medicine who passed away in December 2021, also contributed to this study.

Typically, tumors are collected and exposed to room oxygen, which is about 21 percent. However, different organs in the body have different oxygen levels. For example, the brain has 4.4 percent oxygen, blood 5.3 percent, and liver 5.4 percent. When cancer drugs are used on tumors in the clinical setting, they're still in a patient's body and are not exposed to ambient air.

"The oxygen level in our different parts of the body is almost half of what we find in ambient air," Nakshatri said. "Oxygen can have a different effect on the function of different proteins in the tumors. They may get activated, lose their activity level, get degraded or get stabilized. We wanted to test the tumors in a way that more closely resembles how they are in the body, so we know more about what drugs to use."

Researchers tested three different drugs on two different types of tumors. They split the tumors in half and tested one part in 5 percent oxygen, since that is an average oxygen level in the body, and exposed the other part to room oxygen before testing. They looked at the difference in the cancer stem cells, signaling pathways and how drugs behaved in the different oxygen levels. They found the sensitivy level of the tumor cells was different in 5 percent oxygen versus room oxygen.

"This is a study that is now raising more questions we need to answer," Nakshatri said. "Why do the cells react differently? Are we screening the drugs against cancer cells the right way? If we screen for drugs at the physiologic oxygen level, are we going to find different drugs that we may have missed all these years by doing the experiments at 21 percent oxygen?"

In the future, researchers hope to study the different reactions tumors have to other various oxygen levels, like 1 percent or 20 percent. Nakshatri explained this kind of testing could act as another method of screening to determine a drug's efficacy.

"Suppose we identify a drug with the way we are doing right now in room oxygen, then add another layer of testing in the lab where we keep the cells at the physiologic oxygen level and compare whether the drug is working or not," Nakshatri said. "If it works, then we can move forward to the clinical setting and it increases the chances of the drug being successful."