There have been many advances in therapies against pathways altered in cancer cells. However, there are targeted therapies that remain less effective. Now, researchers from Indiana University (IU) School of Medicine report they have discovered a new way to determine how effective a drug might be against cancer.
Their findings are published in the journal Science Advances in a paper titled, “Tumor collection/processing under physioxia uncovers highly relevant signaling networks and drug sensitivity.”
“Preclinical studies of primary cancer cells are typically done after tumors are removed from patients or animals at ambient atmospheric oxygen (O2, ~21%),” the researchers wrote. “However, O2 concentrations in organs are in the ~3 to 10% range, with most tumors in a hypoxic or 1 to 2% O2 environment in vivo. Although effects of O2 tension on tumor cell characteristics in vitro have been studied, these studies are done only after tumors are first collected and processed in ambient air. Similarly, sensitivity of primary cancer cells to anticancer agents is routinely examined at ambient O2. Here, we demonstrate that tumors collected, processed, and propagated at physiologic O2 compared to ambient air display distinct differences in key signaling networks including LGR5/WNT, YAP, and NRF2/KEAP1, nuclear reactive oxygen species, alternative splicing, and sensitivity to targeted therapies.
“This paper completely changes the way we need to collect tumor tissues and test for drug sensitivity,” said Harikrishna Nakshatri, PhD, 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, PhD, a distinguished professor at IU School of Medicine who passed away in December 2021, also contributed to this study.
“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.”
The researchers tested three different drugs on two different types of tumors. They split the tumors in half and tested one part in 5% oxygen, and the other part in room oxygen before testing. They found the sensitivity level of the tumor cells was different in 5% 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% oxygen?”
The researchers hope to study the different reactions tumors have to other various oxygen levels.
“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 explained. “If it works, then we can move forward to the clinical setting and it increases the chances of the drug being successful.”