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

Descripción del proyecto

Un método innovador para actuar de forma selectiva sobre las células madre tumorales

Nuevas pruebas refuerzan la teoría de que el cáncer se desarrolla y se mantiene por una subpoblación de células tumorales con características semejantes a las de las células madre. Estas células madre tumorales (CMT) suelen estar en estado quiescente, lo que las hace resistentes a los tratamientos convencionales y, por tanto, favorecen la recidiva. En el proyecto SeleCStem, financiado por el Consejo Europeo de Investigación, se pretende desarrollar estrategias innovadoras para actuar de forma selectiva y eficaz sobre las CMT gracias a la enzima aldehído deshidrogenasa (ALDH), que se sobreexpresa en las CMT de diferentes tumores. El equipo de investigación aprovechará la actividad de la ALDH para la liberación selectiva de fármacos dentro de las CMT, que se combinará con la fotoinhibición de la enzima en tumores.

Objetivo

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.
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. 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: we will use the oxidoreductase activity of ALDH to trigger the selective (1) accumulation or (2) release of drugs inside CSCs and (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. We will design these molecules with the aid of docking studies, synthesise them, and assess their ALDH- or light-triggered activation in purified enzyme assays and in CSC spheres.
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 improve cancer treatment and increase complete remission rates.