Inflaming the microenvironment of glioblastoma tumors by ADAR1 inhibition: a two-hit approach for the treatment of brain cancer.

Descripción del proyecto

Inflamación dirigida del microentorno del glioblastoma como un nuevo método terapéutico

El glioblastoma (GB) es la forma más letal de tumor encefálico primario, con una mediana de supervivencia de 14,6 meses y 15 000 diagnósticos nuevos cada año en Europa y los Estados Unidos. Los tratamientos actuales resultan ineficaces debido a la heterogeneidad genética del GB y a la presencia de un microentorno tumoral (MET) inmunodepresor. El proyecto financiado con fondos europeos GlioTarget busca explotar un punto de control de la inmunidad innata para actuar de manera simultánea sobre las células cancerosas objetivo y su MET. La adenosina deaminasa que actúa sobre el ARN 1 (ADAR1) es un componente fundamental de la vía de detección del ARN y recientemente ha surgido como una diana inmuno-oncológica prometedora, dado que existen pruebas de que la pérdida de ADAR1 representa una vulnerabilidad específica de las células cancerosas. El proyecto evaluará el potencial terapéutico de la inhibición de ADAR1 sola o en combinación con el tratamiento habitual e inmunoterapias dirigidas al MET.

Objetivo

The brain is our most precious organ. Not only does it orchestrate vital body functions but it also stores memories and experiences, ultimately defining the core of our human nature. Brain malignancies are particularly disheartening because they disrupt our ability to perform as individuals and hinder our social interactions. Glioblastomas (GBs) represent the most frequent and lethal form of primary brain tumors, with a median survival of 14.6 months and 15,000 newly diagnosed patients per year in Europe and the US. Current therapies invariably fail, likely due to the extreme genetic heterogeneity of GB and the presence of a highly immunosuppressive tumor microenvironment (TME). Here, I propose to exploit an innate immunity checkpoint to simultaneously target cancer cells and their supporting TME. Adenosine Deaminase Acting on RNA 1 (ADAR1) is a central component of the RNA sensing pathway. It edits endogenous self dsRNAs, which would otherwise be recognized as foreign and trigger an aberrant innate immune response. Sensing of foreign nucleic acids results in interferon production which leads to cell-growth arrest, inflammation and immune cell infiltration through the expression of interferon-stimulated genes (ISGs). ADAR1 has recently emerged as a promising immuno-oncology target, with evidence pointing towards ADAR1 loss representing a novel vulnerability of ISG-expressing cancer cells. Despite expressing ISGs, GB tumors have not been evaluated for sensitivity to ADAR1 inhibition to date. I will therefore combine genetic and pharmacologic approaches to inhibit ADAR1 in patient-derived cancer cell lines and pre-clinical mouse models of GB. My aims are: i) to understand the molecular outcomes of ADAR1 inhibition in GB cancer cells; ii) to functionally characterize the TME of GBs upon ADAR1 inhibition; iii) to evaluate the therapeutic potential of ADAR1 inhibition alone and in combination with standard of care therapy and TME-targeted immunotherapies.