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

Worldwide, there are an estimated 240,000 cases of brain and nervous system tumours per year. Glioblastoma (GBM) is the most frequent, aggressive and lethal of these tumours. The disease belongs to a group of heterogeneous and invasive brain tumours derived from glial cells (WHO Grade IV glioma). It has a universally fatal prognosis despite aggressive treatment (surgical resection and adjuvant radio-chemotherapy with temozolomide [TMZ]). 85% of patients die within two years. Despite significant efforts over forty years, clinicians are as yet unable to offer GBM patients a curative therapy. Diverse elements underpin the inherent intractability of GBM. These elements may be considered as “fetters” to improved patient outcomes, and include (1) the diffuse and infiltrative nature of the tumour limiting the scope for surgical removal; (2) rapid proliferative rate of malignant cells; (3) appearance of treatment resistant cell clones, (4) impediment of the blood brain barrier (BBB) precluding access of systemic agents to the brain parenchyma (5) activation of multiple signal transduction pathways/specific gene mutations within the tumour (6) somatic/clonal evolution underpinning intra/inter-tumoural heterogeneity. Relatively ineffective standard of care (SOC), treatment costs between €27,365 and €39,092 per patient resulting in a significant economic burden for the European healthcare sector. The overall research objective of GLIOTRAIN is to identify and interrogate novel therapeutic strategies for application in GBM, while simultaneously implementing state of the art next generation sequencing (NGS) and ‘omics technologies to unravel disease resistance mechanisms. Drawing on unique consortium expertise each Early Stage Researcher (ESR) project will further be underpinned by innovative systems medicine and/or integrative genomic analysis approaches. GLIOTRAIN ESRs will interrogate the “fetters” of GBM which have significantly hampered the translation of research findings to improved patient outcomes. GLIOTRAIN’s largescale, innovative, interdisciplinary and intersectoral research network brings together leading European and international academics, clinicians and private sector partners which cover the fields of tumour biology, genomics, proteomics, drug development, clinical research, data integration, computational modelling and systems biology. GLIOTRAIN will address current unmet needs in the GBM field by interrogating innovative therapeutic strategies and improving the mechanistic understanding of treatment resistance, and will implement both systems-based analysis of known contributors of disease progression, as well as unbiased molecular profiling and analysis approaches. Gender in the proposed research: GLIOTRAIN will benefit both sexes since the disease affects both men and women. However it is noteworthy that astrocytic tumour incidence in males is c. 1.4 higher than in females. Moreover, Prof Hegi (GLIOTRAIN External Advisory Board [EAB]) has further reported that younger female patients with good initial performance status and harboring the MGMT promoter hyper-methylation are over-represented among the 3–5 % of GBM patients who survive over 3 years (long-term survivors). Sex-based analyses of all clinical and ‘omics datasets will be performed within GLIOTRAIN and in vivo studies conducted both in male and female models.