Periodic Reporting for period 1 - GLIORESOLVE (Training the next-generation of European GLIOblastoma (translational) researchers, to RESOLVE precision targeting of the brain tumour microenvironment)
Reporting period: 2022-09-01 to 2024-08-31
GLIORESOLVE is a major multi-disciplinary research and training programme that aims to establish a new cohort of brain cancer researchers with a specific focus on improving treatment outcomes in glioblastoma (GBM). GBM is the most common primary central nervous system malignancy in adults. It carries a poor prognosis, with 85% of patients dying within two years despite standard-of-care treatment (surgical resection, radiotherapy, temozolomide). Despite significant efforts, clinicians remain unable to offer patients a curative therapy. New treatment options, including effective precision medicine therapies, are urgently required. GBM tumours are complex ecosystems of malignant and non-malignant cells (e.g. blood vessels, immune cells, glial cells), together known as the tumour microenvironment (TME), whose behaviour determines therapeutic response. In a previous project (H2020-MSCA-ETN ‘Gliotrain’ [766069]) we hypothesised that interrogation of the GBM TME, including the identification of novel ‘TME subtypes’ could reveal novel contexts of vulnerability and may further provide hints as to which patients might be most amenable to treatment with TME targeted agents, including immunotherapies (White et al., Ann Oncol, 2020). We subsequently established and validated a novel subtyping approach for GBM based on the TME composition (White et al., Ann Oncol, 2023). The research objective of GLIORESOLVE is to leverage the TME subtyping system to establish new therapeutic strategies for GBM, including identification of viable immunotherapeutic approaches. Computational modelling, systems biology and multi-omics approaches are being used to identify novel targets of vulnerability. We are also developing and optimising state of the art in vivo, ex vivo and ‘GBM-on-chip’ models that recapitulate the TME subtypes. These models will be used to test novel rationally selected drugs for precision treatment of GBM based on TME subtype assignment. Cumulatively, the consortium aims to generate sufficient data to support a (post-project) Phase 1b/2 clinical trial to establish a new TME-based precision medicine approach for application in GBM. Overall, GLIORESOLVE is exploiting the urgent clinical need for novel GBM ‘TME-targeting’ precision medicine strategies to train a new generation of highly skilled researchers in the neuro-oncology, immuno-oncology and digital pathology/spatial ‘omics’ domain.
To date core management and technical activities have been implemented as expected. Ten Doctoral Candidates (DCs) have been recruited and enrolled on PhD programmes. All proposed meetings and training events have taken place including two Plenary meetings (June 2023 and 2024) where DCs had the opportunity to introduce themselves and their research projects to the consortium. Three in-person networkwide training events have taken place. Two events focussed on key transferable skills (data management, open science, ethics, research integrity, personal / time management, ‘managing your research project’, communication with a non-scientific audience and poster presentations). The third event was a scientific training event ‘Disruptive Multi-omics and Data Analysis’. We have closely engaged with the external advisory board (EAB) with several EAB members having attended events during reporting period 1. All EAB members will receive a copy of this Report. A key achievement to date has been the identification of putative TME-subtype specific druggable targets using bioinformatics approaches (e.g. Pathway and cell signalling analysis) to analyse multiple in-house and publicly available GBM datasets e.g. TCGA-GBM, CCGA. We expect to identify additional targets and begin to further interrogate these during reporting period 2. The consortium has also developed and optimised several model systems representing the three TME subtypes that will be used during the next reporting period to test rationally selected TME subtype-specific drug combinations. This activity will include the optimisation of novel ex vivo organotypic multicellular spheroids (OMS) with a goal of establishing culture conditions which retains GBM microglial and TME characteristics. Elsewhere, an ex vivo 3-dimensional (3D) co-culture model recapitulating the GBM TME immune compartment (adaptive and innate immune components) has been developed. Another key model being established is a ‘GBM-on-a-chip’ model. Combinations of brain endothelial and supporting cells, in hydrogels have been tested to establish a 3D perfusable vascular network. In vivo models representing the TME subtypes have also established, including orthoptic models amenable to tumour resection, genetically engineered syngeneic models as well as patient derived xenografts. An in silico state of the art algorithm has been optimised which will be used to more accurately model the complex regulatory networks that exist within and between different cell types in GBM. Finally, Ag5-sensitive and resistant GBM cell lines have been identified and employing RNA sequencing and gene network analysis, key molecular mechanisms of resistance have been described.
GLIORESOLVE incorporates a comprehensive and disruptive translational research strategy that goes significantly beyond the state-of-the-art to establish a novel GBM TME-targeting precision medicine platform. In the future this will provide opportunities to deliver immuno- and other precision therapies to brain cancer patients. The potential impact of the programme lies in its ambitious, largescale, innovative, interdisciplinary and intersectoral research network that brings together leading European neuro-oncology researchers, clinicians and private sector partners. The potential for the direct impact of research finding on GBM patients is significant and the consortium is uniquely placed to achieve this impact by virtue of the notable participation of clinical actors (ICM, UHEI, EMC). Overall, we anticipate that findings from GLIORESOLVE will support a (post-project) prospective Phase 1b/2 biomarker driven trial where patients will be assigned to TME classifiers to inform an improved, subtype-specific precision medicine paradigm for application in the GBM setting. Moreover, development and validation of new research models (GBM-on-a-chip, improved animal models) will broadly impact the neuro-oncology research community. The Programme is cultivating the development of new networks and enhancing the quality of existing ones as it functions as a future point of contact and reference for the DCs after graduation. GLIORESOLVE is increasing the internationalisation of participating organisations by reinforcing or creating new international collaborations across the 10 countries represented in the consortium and via the involvement of international collaborators at training events. During reporting period 2, continued collaboration between all consortium members and monitoring of project progress will be important. This will be facilitated through the PCDPs and consortium meetings. SME Beneficiaries have identified that GLIORESOLVE project activities as described in the Grant Agreement (and towards the awarding of the PhD) will be completed as expected, however there may be additional further needs to support full (post-project) exploitation of results. Activities such as business plan development, demonstration in real life environment and testing with end-users will start during the timeframe of the project.