GlioTarget · Inflaming the microenvironment of glioblastoma tumors by ADAR1 inhibition: a two-hit approach for the treatment of brain cancer.
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2021-09-01 → 2023-08-31
- EU contribution
- €191,149
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Inflaming the microenvironment of glioblastoma tumors by ADAR1 inhibition: a two-hit approach for the treatment of brain cancer.
Glioblastomas represent the most frequent and lethal form of primary brain tumours. Tragically, current therapies for glioblastoma patients invariably fail, likely due to: (i) the challenging location of tumours, which precludes complete surgical removal of malignant cells; (ii) their extreme heterogeneity, cancer cells within the same tumour can present distinct genetic profiles and behaviours and respond differently to therapy; (iii) the presence of a highly immunosuppressive tumour microenvironment, i.e. non-cancerous cells which are hijacked by glioblastoma cells to promote cancer progression and therapy resistance. In this project, I propose to simultaneously target cancer cells and their supporting microenvironment as a novel therapeutic approach for glioblastoma treatment. My hypothesis is that by exploiting an innate immunity checkpoint present in all cancer cells, we would target the entire heterogeneity of glioblastoma tumours, impede cancer-cell proliferation and reprogram the communication between cancer cells and their microenvironment to foster an anti-tumoural immune response. ADAR1 is a central player in regulating this immune checkpoint, helping cells to distinguish molecules originating from viral infection from those produced during normal physiological processes and thus preventing aberrant immune responses. Sensing of these foreign molecules leads to cell growth arrest, to impede viral spread, and production of signals that alerts the immune system to fight the infection. I hypothesise that by inhibiting ADAR1 we would promote a similar effect in glioblastoma tumours. Importantly, data from our lab and others has shown that glioblastoma cells present unique features which make them vulnerable to ADAR1 inhibition, while this has little impact in healthy cells. I will therefore test this hypothesis in preclinical mouse models. If validated, this project could lead to a 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.
Data: CORDIS, © European Union
Project 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.
Original text from CORDIS.
Participants
- UNIVERSITE DE LAUSANNE · LAUSANNECoordinatorSwitzerland
Links
Data: CORDIS, © European Union