Why does anti-cancer therapy stop working at a specific stage? Scientists in Israel and the USA believe they have made a breakthrough in understanding why a hopeful anti-cancer therapy fails to destroy tumor cells successfully.
The researchers, whose study is published in PNAS (Proceedings of the National Academy of Sciences), believe their findings may lead to new approaches in overcoming this cul-de-sac.
Suppressing the mTOR (mammalian target Of Rapamycin) protein has been extremely challenging for oncologists.
mTOR plays a key role in regulating vital cell growth processes – it is a bit like a communications command center, receiving external signals from hormones, growth factors and proteins. It then sends out “on” or “off” signals for the cell to grow and divide, seek nutrition, or use that nutrition. mTOR is strongly activated in several solid cancers.
While drugs have been shown to suppress mTOR and have been successful in causing the death of cancer cells in the outer layers of malignant tumors, in clinical trials they have failed in destroying the core of those tumors.
Hypoxia (lack of oxygen) is an almost-universal characteristic of solid tumors that can affect how tumors respond to therapies. Scientists know that the condition of hypoxia affects the behavior of mTOR signaling, but nobody knew what the mechanism was.
Prof. Emeritus Raphael D. Levine, from the Institute of Chemistry at the Hebrew University of Jerusalem, Israel, and scientists from the David Geffen School of Medicine at UCLA and the California Institute of Technology set out to determine what role hypoxia plays on mTOR signaling in model brain cancer systems and whether this could explain why promising mTOR drugs fail.
They used a new microchip technology to measure the mTOR protein-signaling network in cancer cells. They also used a new set of theoretical tools derived from the physical sciences to interpret the results. This dual approach simplified an otherwise extremely complex biological system.
The mTOR biochemical pathway is a complex one
The investigators found that at a specific level of hypoxia, which is typical in solid tumors, the mTOR signaling network switches between two sets of properties. At exactly the moment when the switching over takes places, the theoretical models predicted that mTOR would not respond to mTOR-inhibiting medications.
According to the combined experiment finding, the researchers believe that the switching over might be a kind of phase transition, something not observed before in biological systems.
This phase transition happened very suddenly, and cells being studied stopped responding like they had done before. The authors wrote “In the case of the tumor, the ‘drugging’ of the mTOR ceased, meaning that the tumor was no longer inhibited.”
These results:
- explain why promising mTOR-inhibiting drugs stop working at a specific stage
- “indicate that certain complex biological behaviors, which often confound scientists who are seeking to find effective therapies for human diseases, may be understood by the effective application of experimental and theoretical tools derived from the physical sciences.”
Levine wrote in the PNAS Abstract:
“We find a hypoxia-induced switch within a mammalian target of rapamycin (mTOR) signaling network. At the switching point, mTOR is predicted, and then shown by experiment, to be unresponsive to inhibition. These results may help explain the undistinguished performance of mTOR inhibitors in certain clinical trials.”
In an animal study, scientists from the University of California San Diego, La Jolla, found that mTOR-inhibitors may have adverse effects on heart function in patients with ongoing heart problems.
Written by Christian Nordqvist