The vulnerability of specific tissues to ionising radiation has been linked to the time-varying levels of a tumour-suppressing protein, opening new avenues for cancer combination therapy.
The ability for cells to survive radiation damage has been known to be connected to p53, but tissues with vastly different levels of p53 have been shown to have great differences in sensitivity. In the face of this apparent paradox, researchers from Blavatnik Institute at Harvard Medical School, Massachusetts General Hospital, and the Novartis Institutes for BioMedical Research investigated the behaviour of p53 in irradiated tissues.
“Dynamics matter. How things change over time matters,” said co-corresponding author Galit Lahav, the Novartis Professor of Systems Biology at HMS. “Our ability to understand biology is limited when we only look at snapshots. By seeing how things evolve temporally, we gain much richer information that can be critical for dissecting diseases and creating new therapies.”
Ionising radiation randomly damages a cell’s molecular machinery, causing it to initiate cell death if it is too serious. The arbitrator of cellular suicide is p53, which is also involved in tumour suppression.
The findings opened new avenues for combination cancer therapies, as they discovered that administering a drug that blocks p53 levels from oscillating resulted in tumours in mice being more susceptible to radiation.
Administering to the mice an experimental anti-cancer drug that inhibits MDM2, a protein which degrades p53, they forced p53 to stay elevated. The large intestine, which is normally radiation resistant, showed increased vulnerability.
Testing out this enhanced vulnerability on human tumours transplanted into mice, a significant tumour shrinkage was seen following radiation and then MDM2 inhibitor administration.
Co-corresponding author Galit Lahav, Novartis Professor of Systems Biology, Harvard Medical School explained: “By irradiating first, we force the cancer cells to activate p53, and by adding MDM2 inhibitor on top of that, we can keep p53 active longer. This combination has a much stronger effect than either alone.”
The findings showed the importance of understanding the role of p53 in cancer, the dynamic nature of which is not being looked at in studies testing MDM2. More research into the biological pathways of p53 is called for.
“For a lab studying p53, cancer is always a major motivation. Our goal is to acquire knowledge to help develop better and more efficient therapies,” Lahav said. “Understanding how p53 behaves over time in different conditions is a critical piece of the puzzle.”
Source: News-Medical.Net
Journal information: Stewart-Ornstein, J., et al. (2021) p53 dynamics vary between tissues and are linked with radiation sensitivity. Nature Communications.doi.org/10.1038/s41467-021-21145-z
