Award Title: Targeting biological vulnerabilities of glioblastoma (TARGET-GBM)
Funder: Cancer Research UK

Abstract: Background: We focus on primary glioblastoma (GBM), the most common and aggressive form of adult brain cancer.  Despite increasing knowledge of the genetic and epigenetic changes that underlie the disease, prognosis for GBM patients remains dismal. A new level of understanding of GBM biology is therefore urgently needed. GBMs are driven by neural stem-like cells that exploit developmental pathways to fuel tumour growth and recurrence. Deciphering and targeting the molecular and cellular mechanisms that control GBM cell fate within these developmental/regenerative-like programmes will lead to improved therapies. However, significant challenges exist:    i) The GBM neural stem-like state is sustained by ‘master regulatory’ transcription factors that are thought to be undruggable;   ii) GBM stem cells exist in diverse and poorly understood sub-states of quiescence, dormancy and proliferation;   iii) Cell fate decisions, dormancy and cell proliferation are regulated by complex and ill-defined microenvironmental signals. The TARGET-GBM team will unite three of the UKs leading brain tumour research centres: University of Edinburgh, University College London (UCL), and Institute for Cancer Research (ICR). University of California San Francisco (UCSF) and The Hospital for Sick Children/University of Toronto, will provide missing expertise.    Aims: There are three interlinked Themes:    Theme 1     Transcriptional control of ‘stemness’  Theme 2     Intrinsic and extrinsic control of dormancy/quiescence   Theme 3     Microenvironmental cues: immune-and mechano-regulation    Methods: To tackle these challenges from fresh perspectives we will recruit experts new to the field and leverage our CRUK-funded Brain Tumour Centres of Excellence, and the CRUK-funded Glioma Cellular Genetics Resource (www.gcgr.org.uk). Our vision is to gain a deep integrated understanding of GBM biology and identify new therapeutic targets. We tackle GBM by identifying biological vulnerabilities of GBM across scales (molecular, cell-cell, niche/tissue, physical forces and systemic/immune). This will be achieved by moving back-and-forth between the latest cutting-edge technologies and models (mouse and human), and clinical samples.    All investigators in our team will be supported by five innovative cross-theme platforms (CTPs): quantitative digital pathology (CTP1), whole brain imaging (CTP2), informatics (CTP3), genome engineering (CTP4) and immune profiling (CTP5) (Figure 2). These will be all based in our CRUK Centres, and build upon existing infrastructure, to drive new thinking and new capacity in brain tumour research across the UK.    Outputs: TARGET-GBM will deliver a new integrated and comprehensive picture of how GBM cell fate is controlled. New biology and new targets will emerge. Ultimately, this provides the best chance to identify new cures.

Lay Abstract: Background: We focus on primary glioblastoma (GBM), the most common and aggressive form of adult brain cancer.  Despite increasing knowledge of the genetic and epigenetic changes that underlie the disease, prognosis for GBM patients remains dismal. A new level of understanding of GBM biology is therefore urgently needed. GBMs are driven by neural stem-like cells that exploit developmental pathways to fuel tumour growth and recurrence. Deciphering and targeting the molecular and cellular mechanisms that control GBM cell fate within these developmental/regenerative-like programmes will lead to improved therapies. However, significant challenges exist:    i) The GBM neural stem-like state is sustained by ‘master regulatory’ transcription factors that are thought to be undruggable;   ii) GBM stem cells exist in diverse and poorly understood sub-states of quiescence, dormancy and proliferation;   iii) Cell fate decisions, dormancy and cell proliferation are regulated by complex and ill-defined microenvironmental signals. The TARGET-GBM team will unite three of the UKs leading brain tumour research centres: University of Edinburgh, University College London (UCL), and Institute for Cancer Research (ICR). University of California San Francisco (UCSF) and The Hospital for Sick Children/University of Toronto, will provide missing expertise.    Aims: There are three interlinked Themes:    Theme 1     Transcriptional control of ‘stemness’  Theme 2     Intrinsic and extrinsic control of dormancy/quiescence   Theme 3     Microenvironmental cues: immune-and mechano-regulation    Methods: To tackle these challenges from fresh perspectives we will recruit experts new to the field and leverage our CRUK-funded Brain Tumour Centres of Excellence, and the CRUK-funded Glioma Cellular Genetics Resource (www.gcgr.org.uk). Our vision is to gain a deep integrated understanding of GBM biology and identify new therapeutic targets. We tackle GBM by identifying biological vulnerabilities of GBM across scales (molecular, cell-cell, niche/tissue, physical forces and systemic/immune). This will be achieved by moving back-and-forth between the latest cutting-edge technologies and models (mouse and human), and clinical samples.    All investigators in our team will be supported by five innovative cross-theme platforms (CTPs): quantitative digital pathology (CTP1), whole brain imaging (CTP2), informatics (CTP3), genome engineering (CTP4) and immune profiling (CTP5) (Figure 2). These will be all based in our CRUK Centres, and build upon existing infrastructure, to drive new thinking and new capacity in brain tumour research across the UK.    Outputs: TARGET-GBM will deliver a new integrated and comprehensive picture of how GBM cell fate is controlled. New biology and new targets will emerge. Ultimately, this provides the best chance to identify new cures.

Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: CANCER AND NEOPLASMS