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

Project description

Targeted inflammation of the glioblastoma microenvironment as a novel treatment approach

Glioblastoma (GB) is the most lethal form of primary brain tumours, with a median survival of 14.6 months and 15 000 new diagnoses each year in Europe and the US. Current therapies are inefficient due to the genetic heterogeneity of GB and the presence of an immunosuppressive tumour microenvironment (TME). The EU-funded GlioTarget project aims to exploit an innate immunity checkpoint to simultaneously target cancer cells and their TME. Adenosine deaminase acting on RNA 1 (ADAR1) is a central component of the RNA sensing pathway and has recently emerged as a promising immuno-oncology target with evidence that ADAR1 loss represents a specific vulnerability of cancer cells. The project will evaluate the therapeutic potential of ADAR1 inhibition alone and in combination with standard therapy and TME-targeted immunotherapies.

Objective

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.

Fields of science

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Coordinator

UNIVERSITE DE LAUSANNE
Net EU contribution
€ 191 149,44
Address
QUARTIER UNIL CENTRE - BATIMENT UNICENTRE
1015 LAUSANNE
Switzerland

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Region
Schweiz/Suisse/Svizzera Région lémanique Vaud
Activity type
Higher or Secondary Education Establishments
Links
Total cost
€ 191 149,44