Cancer treatment still represents a major challenge, with continuous increase in incidence, morbidity and relapse. It is now accepted that resistance to conventional chemotherapy is often caused by a small population of cells that can self-renew and differentiate into the cells that constitute the bulk of the tumour. These are generally known as cancer stem cells (CSCs). CSCs usually adopt a quiescent state, which is not affected by standard anti-proliferative chemotherapy; most current treatments are able to eliminate the bulk of the tumour mass, but leave CSCs unaffected. This is thought to be the main cause of resistance to cancer treatment and tumour regrowth. Since the CSC concept was first demonstrated, the field of CSCs has seen an enormous advance, and to date CSCs have been identified, isolated and characterised from various human cancers. However, despite growing knowledge on the existence of these cells, finding effective and safe drugs against them is challenging.
In order to achieve higher complete remission rates after cancer treatment, eliminating CSCs is essential. One of the challenges in finding suitable drugs is their high similarity to healthy stem cells, which makes it difficult to design selective drugs that do not cause deleterious side effects in healthy tissues.
The lack of selectivity of small molecule drugs, which often leads to side effects, is caused by the inability to control their biological activity in time and space; this remains a major issue in the care of cancer patients amongst others. Photopharmacology aims to use light as an external non-invasive element to control drug activity, allowing for the activation of drugs with high spatial and temporal precision. It is based on the design of small molecules that have either a photoswitchable (reversible) or photocaging (irreversible) moiety, which delivers the active molecule only during/upon illumination with a particular light wavelength and intensity.
Within PhotoStem, we proposed that the use of photopharmacology techniques could overcome the challenge of differentiating between cancer and healthy stem cells. The overall aim was to design drugs that change their structure with light, and which can eliminate CSCs only after illumination. In the future, by illuminating only the tumour area, we would achieve tumour eradication, while leaving healthy stem cells of other tissues unaffected.
More specifically, the objectives were to firstly establish a proof of concept by (1) designing photoswitchable inhibitors of a well-known target, (2) testing their effect in CSCs in vitro and (3) in zebrafish; and secondly to (4) design light-activable inhibitors of a less explored pathway.
After this two-year fellowship, we have been able to establish a proof of concept in vitro. We first showed that photoswitchable inhibitors of histone deacetylases can eliminate CSC-enriched cell lines only under light conditions. We then also showed that a photocaged autophagy inhibitor could eliminate the formation of CSC spheres only after illumination. This represents an in vitro proof of concept that CSCs can be controlled with light using both photoswitchable and photocleavable molecules.
