Light switch makes cancer vulnerable to attack

Tumour cells can lapse into a sleep-like state and thereby evade the destructive effect of cancer drugs. In some types of the disease, such as certain forms of lung cancer, this state is triggered by stress hormones in the body. Inside the cancer cells, glucocorticoid receptors recognise the hormones, and the cells respond by lapsing into a state in which they undergo barely any division. This renders many treatments ineffective. Scientists are attempting to switch off these receptors with a view to waking the cancer cells up from sleep – making them vulnerable to attack. 

Light restricts impact to tumour 

The problem is that every cell in our body has glucocorticoid receptors, which perform important functions – including in reducing inflammation and for the immune system. Eliminating all these receptors throughout the body would have disastrous side effects, so there is a need for a highly specific method that only destroys the glucocorticoid receptors of tumour cells. 

Researchers from ETH Zurich have now found a solution by developing a system that induces the destruction of these receptors. Light can be used to selectively neutralise the system’s effect in surrounding healthy tissue so that the impact is limited to the tumour. “This system is based on existing medical technology and therefore offers a realistic prospect of localised therapies,” says Robin Scheuplein, joint first author of the publication and a doctoral student in the research group led by Katharina Gapp, Professor of Epigenetics and Neuroendocrinology. 

Tagging ensures rapid disposal of receptors 

For their approach, the researchers used a recycling system that exists naturally in the body. This system detects defective proteins and tags them for disposal by attaching a small molecule – a “rubbish” label, so to speak. Proteins labelled in this way are then broken up. The researchers have now modified this process specifically for the disposal of glucocorticoid receptors on tumour cells. 

To do so, they built a switch made up of three parts: a sub-unit that binds to the receptor, a flexible connecting piece, and another sub-unit that binds to the enzyme responsible for attaching the rubbish label. The trick lies in the chemical design of the connecting piece: in normal lighting conditions, it is stretched so that the enzyme is at the correct distance from the receptor in order to mark it. The cell therefore receives the signal to break up and dispose of the receptor. When exposed to light of a given wavelength, the connecting piece becomes kinked. As a result, the enzyme and receptor no longer have the correct relative positioning to attach the rubbish labels.  

Lung cancer cells woken from sleep in the lab 

This scientific development was made possible by a collaboration between various research groups at ETH Zurich. For these experiments, Professor of Organic Synthesis Erick Carreira and his team produced multiple connecting pieces. When incorporated into the switch, two of these pieces showed exactly the desired characteristics during testing. Namely, light could be used to flip the switch between a form that induces degradation of the receptor and one that does not. 

The aim is to apply this switch in high-precision localised cancer treatment. To this end, it is injected into the tumour, and light is then used to specifically turn off all switches that migrate from the tumour into the healthy tissue. “Activity can therefore be strictly limited to the tumour core, preserving the surrounding tissue and causing significantly fewer side effects. The effect is reversible and can be controlled precisely,” says Scheuplein. 

In lab cultures of lung cancer cells, the researchers have already succeeded in demonstrating the expected biological effect, with the active substance leading to a rapid breakdown of the tumour cells’ glucocorticoid receptors. An analysis of genetic activity also showed that the cells are woken from their dormant state as a result. “Of course, this will now need to be verified in living organisms as well,” says Scheuplein. 

Applications in breast and prostate cancer 

Moreover, the researchers still need to optimise the system for applications in cancer therapy. As light only penetrates a few millimetres into tissue, the light source must be placed close to the tumour boundaries in order to establish the protective optical barrier. In the case of lung cancer, for example, this could easily be achieved using an endoscope. For deeper-seated tumours, the research teams want to develop switches that respond to longer wavelengths, such as near-infrared, which penetrate deeper and more gently into the tissue.  

“We’ve developed a modular system that we can also use to switch off other receptors,” explains Scheuplein. For example, receptors of interest for clinical applications include the oestrogen receptor in the case of hormone-dependent breast cancer and the androgen receptor in advanced prostate cancer. The system is already ready for use in research in order to clarify complex signalling pathways in cancer biology.