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Exploiting GLIOblastoma intractability to address European research TRAINing needs in translational brain tumour research, cancer systems medicine and integrative multi-omics

Periodic Reporting for period 2 - GLIOTRAIN (Exploiting GLIOblastoma intractability to address European research TRAINing needs in translational brain tumour research, cancer systems medicine and integrative multi-omics)

Reporting period: 2019-09-01 to 2021-08-31

Worldwide there are c. 240,000 cases of brain and nervous system tumours per year. Glioblastoma (GBM) is the most frequent and aggressive. Despite significant efforts clinicians remain unable to offer curative therapy. 85% of patients die within 2 years despite aggressive treatment (surgical resection + radio-chemotherapy + temozolomide). Diverse elements underpin the intractability of GBM including its infiltrative nature, rapid proliferative rate, treatment resistance, the blood brain barrier impeding access of drugs, activation of multiple signal transduction pathways/specific gene mutations and intra/inter-tumoural heterogeneity. New treatment options and effective precision medicine therapies are urgently required. The objective of GLIOTRAIN was to exploit the intractability of GBM to address European applied biomedical research training needs, to identify novel therapeutic strategies for application in GBM and unravel disease resistance mechanisms.
WP1 focused on the development of new, rationally designed therapeutic strategies using systems medicine, integrative ‘omics, state-of-the-art disease models and drug delivery methods. 4 deliverables were submitted; D1.1 Protein-based analysis of GBM signalling networks using mathematical systems modelling to predict treatment responsiveness [Tasks 1.1 and 1.2]; D1.2 the efficiency of new methods i.e. ultrasound, to deliver GBM targeted therapies across the BBB [Task 1.4]; D1.3 efficacy of new GBM therapeutic approaches in vitro and in vivo [Tasks 1.3 1.4 1.6 1.7]; D1.4 a genomic driven approach to identify molecular biomarkers and therapeutic targets for glioblastoma [Task 1.8-1.9]. Another key result was the establishment of a novel subtyping approach for IDHwt GBM based on the composition of the tumour microenvironment (TME) [Task 1.5].

Projects in WP2 utilised in silico models, ‘omic technologies and exploited computational/integrative data analysis methods to interrogate intratumoural heterogeneity and cancer evolution. 4 deliverables were submitted; D2.1 novel GBM multi-scale stochastic mathematical models [Task 2.2]; D2.2 utility of GLIOscreen® culture platforms to support proteogenomic discovery of novel GBM treatment resistance pathways [Task 2.5]; D2.3 scRNA sequencing and spatial transcriptomic methods to interrogate GBM intra-tumoural heterogeneity and response to therapies targeting the tumour microenvironment [Tasks 1.6 2.3 2.4]; D2.4 putative novel GBM therapeutic targets to overcome resistance, identified by integrative multi-omics and computational modelling [Tasks 2.1 2.6 2.7].

WP3 (Training) All proposed training events were undertaken during the course of the project. PCDPs were developed and reviewed 6-monthly. 10 deliverables relating to network wide and project specific training were submitted.
WP4 (Management) 15 ESRs were recruited for 36 months. All proposed meetings took place (online where in person meetings were restricted). 22 deliverables relating to the consortium agreement, data management plan, supervisory boards and subcommittees, recruitment, project and financial management and annual meetings were submitted.

WP5 (Dissemination and communication) progressed well during the project despite the impact of COVID-19. All ESRs presented at national or international conferences. PIs regularly presented at large neuro-oncology meetings (e.g. SNO, EANO). 7 deliverables reporting dissemination, outreach and communication were submitted in a timely manner. The final network conference was attended by c. 45 external participants. Overall GLIOTRAIN participants published 21 peer reviewed publications during the course of the project.

WP6 (IPR) was implemented via review of project related IP at each annual meeting. 2 deliverables relating to IP potential in each project were submitted. Ongoing projects will continue to be monitored for emerging IP.
7 deliverables relating to WP7 (Ethics) were submitted. All ethics documentation was in place prior to the commencement of an activity that raised an ethical concern and documents were collated centrally.
GLIOTRAIN united multiple disciplines, including tumour biology, multi-omics, drug development, clinical oncology research, computational modelling and systems biology. Our approach provided a comprehensive research strategy that went beyond the current state-of-the-art. Novel multi-omic analyses enabled simultaneous integration of gene expression, genomic instability and epigenetic data, providing a clearer insight into the cellular diversity and genetic heterogeneity present in the GBM TME. Single cell approaches revealed the complexity of biological systems. Spatial transcriptomics allowed gene expression profiles of single cells to be pinpointed to a specific location. Spatial mapping supported the identification of cellular niches and revealed location-dependent heterogeneous cell interactions.

A key result to emerge from GLIOTRAIN has been the identification of a novel subtyping approach for IDHwt GBM. Indeed the consortium highlighted the importance of establishing a precision medicine paradigm for Grade IV glioma patients in a 2020 white paper publication (‘New hints towards a precision medicine strategy for IDH wild-type glioblastoma’ White et al, Ann Oncol 2020 Dec;31(12):1679-1692). Studying IDHwt GBM subtype specific differences across the TME has revealed putative novel contexts of vulnerability. Importantly, initial results suggest a subtype specific response to immunotherapeutics. A high impact collaborative manuscript describing these data will be submitted in Q2 2022. Moreover, data generated during GLIOTRAIN have already supported multiple large scale follow-on collaborative funding initiatives to facilitate further interrogation of the biology of novel “GLIOTRAIN subtypes” and to validate the subtypes in additional datasets. Ultimately, in the coming years we aim to develop sufficient data to support a prospective Phase 2 biomarker-driven trial where GBM patients would be subtyped according to TME composition and data used to inform treatment regimens.

Overall the investigation of new biomarkers, stratification models, drug combinations and therapeutic strategies in the GBM setting undertaken during GLIOTRAIN has the potential to impact patients, clinicians and healthcare systems. The proposed biomarker-driven Phase 2 trial may lead to a new personalised treatment strategy where patients may benefit from reduced hospital time and by the avoidance of toxicities associated with ineffective therapies.

To date, 4 ESRs have successfully defended their theses. The remaining ESR projects continue beyond the end of the Action with students financially supported by their respective institutions. GLIOTRAIN has successfully trained 15 ESRs in an environment that spans translational research, medicine and computational biology, who will progress research findings towards improved patient outcomes.
GLIOTRAIN Consortium October 2019
GLIOTRAIN Concept Figure