ADAR1 inhibition: Hijacking an innate immune mechanism present in all malignant cells 

Fast facts

• Official title: Inflaming the microenvironment of glioblastoma tumors by ADAR1 inhibition: a two-hit approach for the treatment of brain cancer
• Lead researcher: Dr. Angel Alvarez-Prado
• Where: University of Lausanne, Switzerland
• When: October 2022 – September 2025
• Cost: £224,511 over three years
• Research type: Glioblastoma, High Grade Glioma, Imaging, Immunotherapy, Quality of Life, Radiotherapy, Survivorship, Tumour Microenvironment
• Award type: Future Leaders

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Glioblastomas are incurable brain tumours. They are difficult to treat given their location, their considerable heterogeneity (each cell has a peculiar identity that makes that cell different from all the others) and the ability of glioblastoma cells to re-educate the immune system in their favour. Standard of care therapy targets cancer cells. New therapeutic strategies have instead advanced towards exploiting the immune system to fight glioblastoma tumours. So far targeting either the cancer cells or the immune system has not significantly changed the survival of patients. Dr Alvarez-Prado’s proposed project emerges from the innovative perspective of simultaneously targeting both cancer cells and their supporting immune microenvironment. 

What is it?

Dr Alvarez-Prado will focus his work on a component of cancer cells called ADAR1 (Deaminase Acting on RNA1), which helps cells to distinguish molecules originating from viral infection from those produced during normal physiological processes. A chain of molecule-molecule interactions take place as a defence mechanism (immune response) when foreign molecules of viral origins are detected. The immune response involves the production of signals that alerts the cells of the immune system as well as stopping any growth process in the cell affected (with viral infection). Dr Alvarez-Prado’s research aims to simultaneously attack cancer cells from the inside and outside. The hypothesis is that getting rid of ADAR1 in cancer cells would confound cancer cells’ defence mechanisms. The lost ability to recognise molecules produced during normal physiological processes would lead to an increase vulnerability of cancer cells. This would increase the possibility that cancer cells would call for an immune response against a virus without the virus being present. 

In his research, Dr Alvarez-Prado will take advantage of glioblastoma mouse models (standard practice in the first stages of brain tumour research). In one case, the glioblastoma mouse models will be bearing distinct genetic alterations (changes in cell’s DNA) to avoid the production of ADAR1 in cancer cells.  In another case, the glioblastoma mouse models will be treated with a drug inhibiting the function of ADAR1.  Dr Alvarez-Prado will visualize and follow tumour progression using a powerful imaging technique called magnetic resonance imaging. Dr Alvarez-Prado will also use a variety of techniques used in biology (e.g., flow cytometry, immunofluorescence analysis, fluorescent activated cell sorting, RNA sequencing) to characterize the dynamics of immune cells around the brain tumour, before and after inhibition of ADAR1. 

The microenvironment around glioblastoma cells is often highly immunosuppressive. This means that it can inhibit the ability of immune cells to fight the tumour. TME-targeted immunotherapies are designed to inhibit or activate specific signalling pathways or immune cells. By reprogramming the immune microenvironment to fight cancer cells, TME-targeted immunotherapies could overcome the immunosuppressive nature of the microenvironment and enhance the effectiveness of ADAR1 inhibition. Dr Alvarez-Prado will evaluate the therapeutic potential of ADAR1 inhibition in combination with TME-targeted immunotherapies, which could have a synergistic effect, improving the overall effectiveness of the therapy. 

Why is it important?

The potential impact of this research is significant, since the compound Dr Alvarez-Prado will use to inhibit ADAR1 is structurally very similar to that in a drug already being used to treat other cancers. This could accelerate the translation of the findings into clinical trials. 

By exploiting a vulnerability present in glioblastoma cells, the project has the potential to lead to more effective and less toxic treatment. 

Furthermore, he will test the inhibition of ADAR1 in combination with other standard of care treatments. Dr Alvarez-Prado’s project is critical in developing new therapeutic approaches that simultaneously target cancer cells and their supporting microenvironment. 

Who will it help?

Dr. Alvarez-Prado’s project has the potential to benefit people with glioblastoma, their families, and healthcare professionals. Successful outcomes could lead to more effective treatments with fewer side effects, improving quality of life for people diagnosed with glioblastoma. Additionally, understanding the underlying biology of glioblastoma and using state-of-the-art techniques to study it will help inform future treatments.  

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This project could lead to more effective treatment for patients, by simultaneously attacking cancer cells from the inside and outside, and would be less toxic, as it exploits a vulnerability present within glioblastoma cells. If our approach is successful, we envision a timescale of 10 years for all three phases of clinical trials to be completed and a potential new drug to be licensed and made available to patients.

Dr. Alvarez-Prado