Chemogenetics Application and PhotoActivated ChemoTherapy to study Multidrug Resistance in Glioblastoma

Cancer therapy faces significant challenges due to multidrug resistance (MDR), which reduces the effectiveness of chemotherapeutic agents.

A key factor influencing MDR is the altered redox state within cancer cells, characterized by varying levels of reactive oxygen species (ROS). Understanding the dynamics of ROS is crucial, as they can both promote and inhibit tumor progression.

Glioblastoma, a highly aggressive and treatment-resistant brain cancer, exemplifies the challenges associated with MDR, often exacerbated by a hypoxic tumor microenvironment and elevated ROS production.

This project aims to investigate the role of ROS in MDR by integrating PhotoActivated ChemoTherapy (PACT) and recombinant D-amino acid oxidase (DAAO), a chemogenetic tool that is able to generate hydrogen peroxide (H2O2), the most stable ROS, within specific cellular compartments.

PACT is an innovative anticancer treatment utilizing ruthenium-based (Ru) compounds that are selectively activated by red light in an O2-independent manner, minimizing damage to healthy tissues.In this project, I will implement DAAO to introduce controlled levels of H2O2 into glioblastoma cells, and then treat the cells with PACT, targeting NAMPT, a protein involved in the recycling of NAD+.

I will correlate cancer cell resistance to PACT treatment with ROS levels, which will be monitored via Genetically Encoded Fluorescent Indicators (GEFIs).

The project includes i) developing targeted ROS generation systems during a secondment at the nearby hospital, ii) exploring cellular adaptive responses, and iii) conducting in vivo mouse studies to validate the results from in vitro experiments. This project aims to combine chemogenetic applications and PACT for the first time.

This innovative research has the potential to provide significant insights into the role of ROS in cancer therapy resistance, and to propose effective strategies to overcome MDR, thereby advancing glioblastoma treatment.