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

Reporting period: 2017-09-01 to 2019-08-31

Worldwide, there are c.240,000 cases of brain and nervous system tumours per year. Glioblastoma (GBM) is the most frequent and aggressive, with a universally fatal prognosis. 85% of patients die within 2 years despite aggressive treatment (surgical resection + adjuvant radio-chemotherapy with temozolomide [TMZ]). Relatively ineffective treatment costs c.€40,000 per patient, a significant economic burden across Europe. Despite significant efforts, clinicians remain unable to offer patients a curative therapy. Diverse elements underpin the intractability of GBM, including its infiltrative nature, rapid proliferative rate of malignant cells, treatment resistance, the blood brain barrier (BBB) 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 overall objective of GLIOTRAIN is to identify novel therapeutic strategies for application in GBM, while simultaneously unravelling disease resistance mechanisms. Research activities incorporate applied systems medicine approaches, integrative multi-omics and leverage state of the art technologies implementing the latest clinically relevant models.
Core management and technical activities have been implemented and a proactive communication and dissemination programme developed. 15 ESRs were recruited and enrolled on PhD programmes. The consortium dealt efficiently with delays encountered due to GDPR legislation. All appropriate ethics processes are in place. GBM patient samples were identified and shipped from local biobanks to central sequencing laboratories. Samples have undergone whole genome sequencing and RNA sequencing. Methylation sequencing and reverse phase protein array analysis is ongoing. All sequencing and clinical data is transferred to the central GLIOTRAIN tranSMART database for curation and sharing.

WP 1 focuses on the development of new, rationally designed therapeutic strategies using systems medicine, integrative ‘omic approaches, state-of-the-art disease models and drug delivery methods. To this end, cyclin dependent kinase inhibitors and combination treatment with IZI1551 (a TRAIL-inhibitor) plus marizomib have shown early pre-clinical promise. Moreover, two new TRAIL-variants were constructed and have been shown to induce apoptosis in cell lines. Using a drug-repurposing approach, several clinically approved drugs were identified that may confer benefit in GBM. Towards the development of improved GBM preclinical models, a surgical resection xenograft model and novel syngeneic models have been established. The latter have been employed in early studies using ultrasound-mediated disruption of the BBB to improve drug delivery to the tumour. Projects in WP 2 utilise in silico models, the newest ‘omic technologies and exploit computational/ integrative data analysis methods to interrogate intratumoural heterogeneity and cancer evolution. Single-cell RNA-seq and bulk RNA-seq approaches have confirmed heterogeneity across GBM patient tumour samples and identified major cell types and subtypes, providing information on the diverse GBM tumour microenvironment.

The utility of patient derived orthotopic xenograft models as reliable platforms for translational research was confirmed by scRNA-seq which indicated stable gene expression profiles following implantation and passage through rodents. A novel syngeneic model which reflects the genetic heterogeneity observed in GBM patients has also been developed.

Towards the interrogation of resistance mechanisms, a non-Darwinian mathematical model has identified a novel strategy for overcoming MGMT mediated TMZ resistance. Another model that uses machine learning algorithms to identify survival features of patients using gene expression profiles predicts short-term and long-term survival. Signal transduction networks driving treatment response in patients have also been identified. Early results indicate that key master regulators include those involved in epithelial-mesenchymal transition. Finally, key signalling pathways (PI3K/AKT, RB and TP53) have been incorporated into a GBM disease map, which will be used to identify key pathways involved in disease progression and resistance.
GLIOTRAIN unites multiple disciplines, including tumour biology, multi-omics, drug development, clinical research, computational modelling and systems biology. Our approach provides the foundation for a comprehensive research strategy that goes beyond the current state-of-the-art. New biomarkers, stratification models, drug combinations and therapeutic strategies discovered in the GBM setting may also have significant additional impact within the broader oncology space.

Novel multi-omic analyses allow for the simultaneous integration of gene expression, genomic instability and epigenetic data, providing a clearer insight into the cellular diversity and genetic heterogeneity present within the GBM tumour microenvironment. scRNA-seq provides expression profiles of individual cells from tumour samples and reveals the complexity of biological systems. Spatial transcriptomics allows gene expression profiles of single cells to be pinpointed to a specific location in a biological tissue. Spatial mapping supports the identification of cellular niches and reveals location-dependent heterogeneous cell interactions. The combination of scRNA-seq data with spatial transcriptomics represents a key technology towards understanding GBM heterogeneity. Combining ‘omics data with computational modelling approaches enables researchers to determine drug-targetable vulnerabilities.

A number of clinically relevant models have been established variously using patient derived cells, 3D cell cultures, syngeneic/ xenograft orthotopic implantation and intracranial resection techniques. These models are employed to investigate the efficacy of promising therapeutics including cyclin-dependant kinase inhibitors, BCAT inhibitors, TRAIL-inhibitors, and immunotherapies. Moreover, new methods that employ ultrasound to improve delivery of drugs across the BBB are in development.

Ultimately, GLIOTRAIN will identify novel treatment strategies for GBM, and provide insights into disease heterogeneity towards an improved personalised medicine approach.

The benefits of GLIOTRAIN will ultimately be experienced by patients, clinicians and across healthcare systems. Patients may ultimately benefit from reduced hospital time and through the avoidance of toxicities associated with ineffective therapies. The burden on care-givers and patient social networks will be reduced. Significant savings in healthcare realized through better treatments will release funding for other social assets across Europe and beyond.
The GLIOTRAIN Consortium - October 2018
GLIOTRAIN Concept Figure