Project description DEENESFRITPL 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. Show the project objective Hide the project objective 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 natural sciencesbiological sciencesbiochemistrybiomoleculesnucleic acidsmedical and health sciencesclinical medicineoncologynatural sciencesbiological sciencesgeneticsRNAmedical and health sciencesbasic medicineimmunologyimmunotherapy Programme(s) H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions Main Programme H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility Topic(s) MSCA-IF-2019 - Individual Fellowships Call for proposal H2020-MSCA-IF-2019 See other projects for this call Funding Scheme MSCA-IF-EF-ST - Standard EF Coordinator UNIVERSITE DE LAUSANNE Net EU contribution € 191 149,44 Address Quartier unil-centre bâtiment unicentre 1015 Lausanne Switzerland See on map Region Schweiz/Suisse/Svizzera Région lémanique Vaud Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00
