Some cancer cells can enter a dormant, sleep-like state that helps them survive treatment. Instead of continuing to grow and divide, these cells become largely inactive, allowing them to evade the effects of many cancer drugs.
In certain forms of cancer, such as some types of lung cancer, stress hormones can cause this response. Special proteins called glucocorticoid receptors detect these hormones in tumor cells. Once activated, the receptor can force cells into a dormant state, dramatically slowing cell division. As a result, the effectiveness of many treatments is significantly reduced.
Researchers have been looking for ways to disable these receptors to wake cancer cells from their dormant state, making them easier to target and destroy.
Targeting tumor cells using light
The big challenge is that glucocorticoid receptors are present throughout the body, not just in cancer cells. These receptors play an important role in controlling inflammation and supporting normal immune system function.
Therefore, eliminating glucocorticoid receptors anywhere in the body can have serious side effects. Therefore, successful treatment must target tumor cells while leaving healthy tissue largely unaffected.
Scientists at ETH Zurich have developed a potential solution. They created a system that causes the destruction of glucocorticoid receptors in tumor cells while allowing researchers to use light to selectively turn off processes in nearby healthy tissue.
“This system is based on existing medical technology and therefore offers a realistic prospect for local therapy,” says Robin Schoplein, co-lead author of the study and a doctoral student in the research group led by Professor of Epigenetics and Neuroendocrinology Katharina Gapp.
Harness your body’s protein recycling system
The new approach takes advantage of natural cell recycling processes. Normally, cells identify damaged or defective proteins and mark them for disposal by attaching small molecular tags to them, essentially labeling them as cellular waste. Once tagged, those proteins are degraded and removed.
The ETH Zurich team adapted this process to specifically target glucocorticoid receptors within tumor cells.
To accomplish this, the researchers designed a molecular switch consisting of three components. Some bind to glucocorticoid receptors. The other binds to an enzyme that places a disposal tag. There is a flexible connector between them.
Connectors are the key to your system. Under normal lighting conditions, the enzyme remains extended, placing the enzyme close enough to label the receptor for destruction. The cells are then destroyed and the receptors removed.
However, the connector bends when exposed to certain wavelengths of light. This change prevents proper alignment of the enzyme and receptor, stopping the tagging process and preventing destruction of the receptor.
Awakening dormant lung cancer cells
The technology resulted from a collaboration between several research groups at ETH Zurich. As part of the project, a team led by organic synthesis professor Erick Carreira created multiple versions of the connector component.
Testing shows that two of these connectors work as intended. Light could reliably switch the system between an active state that destroys glucocorticoid receptors and an inactive state that leaves them alone.
The long-term goal is to use this technology for precision cancer treatment. The researchers envision injecting the switch directly into tumors and using light to inactivate molecules that travel to surrounding healthy tissue.
“The activity is therefore strictly restricted to the center of the tumor, preserving the surrounding tissue and significantly reducing side effects. The effects are reversible and can be precisely controlled,” says Scheuplein.
The research team observed the expected biological response in laboratory cultures of lung cancer cells. This treatment rapidly destroyed glucocorticoid receptors within tumor cells. Analysis of gene activity also showed that the cells emerged from a dormant state.
“Of course, we’ll need to test this in vivo in the future,” says Schoplin.
Possibility of application beyond lung cancer
The researchers emphasize that further development is still needed before this system can be used in cancer patients.
One limitation is that light can only penetrate a few millimeters into tissue. To create the desired protective border around the tumor, the light source should be placed close to the treatment area. For example, in the case of lung cancer, this may be achieved endoscopically.
For tumors located deep in the body, the researchers hope to develop a version of the switch that responds to longer wavelengths of light, such as near-infrared light, that can penetrate tissues farther and more gently.
This platform has potential applications beyond the glucocorticoid receptor.
“We developed a modular system that can also be used to switch off other receptors,” Scheuplein explains.
Potential targets include estrogen receptors, which are involved in hormone-dependent breast cancer, and androgen receptors, which are associated with advanced prostate cancer. The system is also ready for use as a research tool to help scientists better understand the complex signaling pathways involved in cancer biology.
