Exploiting the activity of the ALDH enzyme to develop highly selective drugs for cancer stem cells

Introduction

Despite huge advances in cancer treatment, resistance to chemotherapy is still common. It is now well established that a small population of cells named cancer stem cells (CSCs) have high tumorigenicity and are able to initiate and maintain a tumour. CSCs usually remain in a quiescent state that is not affected by standard chemotherapy; thus, they are often responsible for treatment resistance and relapse. There is a clear need to find effective treatments against CSCs to fully eradicate the tumour. However, the close similarities of CSCs to healthy stem cells hinders the identification of selective drugs.

Emerging Drug Modalities

In the last years, new drug modalities are emerging to provide therapeutic options for challenging targets and diseases, expanding the drug discovery landscape. In line with these trends, SeleCStem aims to develop innovative chemical biology strategies to target CSCs in a safe and effective manner.

Targeting CSCs

It will exploit the activity of the enzyme ALDH, which is overexpressed in CSCs of many cancer types, to obtain selective drugs using three orthogonal strategies:

1. Use the oxidoreductase activity of ALDH to trigger the selective accumulation of drugs inside CSCs.
2. Use the oxidoreductase activity of ALDH to trigger the selective release of drugs inside CSCs.
3. Use external light to inhibit ALDH only in the tumour area.

Successful strategies will be combined at the end of the project to overcome potential limitations of the individual approaches, hence massively increasing the drugs' selectivity and efficacy.

Development and Assessment

We will design these molecules with the aid of docking studies, synthesize them, and assess their ALDH- or light-triggered activation in purified enzyme assays and in CSC spheres.

Conclusion

Overall, we will develop the proof of concept of unprecedented approaches to eliminate CSCs with outstanding precision, thus overcoming some of the limitations of conventional small molecules going beyond state-of-the-art chemical biology. Our ultimate goal is to contribute to improving cancer treatment and increasing complete remission rates.