A BMI1/CHD7 signature in medulloblastoma with poor prognosis.

Lead Research Organisation: Queen Mary, University of London
Department Name: Blizard Institute of Cell and Molecular

Abstract

Brain tumours account for a large proportion of childhood tumours. Medulloblastomas are the most common brain cancers seen in young children. They are malignant tumours formed from poorly developed cells at a very early stage of their life. They develop in a region at the back of the head called the posterior fossa in the region of the brain called the cerebellum, but may spread to other parts of the brain. Very rarely, medulloblastomas may spread to other parts of the body. The main treatments available to children with medulloblastomas today are surgery, radiotherapy or chemotherapy. These treatments can be effective and kill the tumour cells in a proportion of patients; however they almost invariably also result in severe side effects which are particularly damaging in young children as the brain is still growing. These side effects mainly affect a child's physical and intellectual development with hearing and visual disturbances, growth and hormonal changes, reduced fertility, behavioural changes, learning problems, difficulties with coordination and secondary cancers. A report recently compiled by the New Philanthropy Capital, has identified brain tumours as one of the worst funded cancer, the cumulative research spend on brain tumours between 2002 and 2011 was less than 1% of all NCRI research spend.

We have recently employed powerful new genetic approaches to identify specific molecular changes that characterize a particularly aggressive subtype of medulloblastomas for which no specific treatment exists. We have established cells from these tumours that can be grown in the laboratory and we have the ability to produce mice that develop the same types of tumours. We will use state-of-the-art methods to study the mechanisms responsible for the formation and growth of these tumours. These studies will lead to the identification of new genes and pathways that can be targeted to stop or reduce tumour formation and growth. We will target these genes and pathways to identify the ones that show most promise as therapeutic targets, which will represent the first important steps towards developing effective, new generation treatments for one of the most aggressive subtypes of this devastating disease.

Technical Summary

Medulloblastomas are the most common malignant brain tumours of childhood, accounting for a quarter of all cancer-related childhood deaths. Genome-wide expression, copy number analysis and whole genome sequencing have significantly advanced our understanding of the molecular pathogenesis of these tumours, identifying four distinct subgroups affecting prognosis and predicting response to therapy. Despite improvements in the clinical treatment of these tumours, the outlook for aggressive subgroups remains bleak, while survivors often suffer from pronounced neurocognitive delays resulting from the surgical resection of the tumour and subsequent chemotherapy/radiotherapy.

We have identified a subset of medulloblastomas that exhibit a novel BMI1highCHD7low molecular signature associated with reduced overall survival. Our initial analyses of primary medulloblastoma cells of this particular subgroup and CHD7-deficient primary mouse granule neuron progenitors have led to the identification of three potential mechanisms of BMI1-CHD7 convergence. We will use these cells and novel mouse models to test the biological relevance of these molecular mechanisms in medulloblastoma development. In addition, we will employ state-of-the-art, unbiased, genome-wide approaches (RNA-seq, ChIP-seq and ATAC-seq) to identify novel tumour-promoting pathways in medulloblastomas displaying this signature. The significance of these genes and pathways in tumour formation and growth will be assessed by over-expression and knock-down experiments in human medulloblastoma cells and xenografts.

Comparative analysis of the candidate genes identified in the experimental models with the human datasets followed by functional validation of the most promising candidates in human primary medulloblastoma cells will lay the basis for future high- throughput drug screening to identify new single-agents or combinatorial therapeutics with anti-tumour properties.

Planned Impact

A report recently compiled by the New Philanthropy Capital, has identified brain tumours as one of the worst funded cancer, the cumulative research spend on brain tumours between 2002 and 2012 was less than 1% of all NCRI research spend. The severe lack of funding for brain tumour research has been repeatedly highlighted in the media. Investment in basic research with translational potential is urgently needed to tackle this devastating disease.

Brain tumours account for a large proportion of childhood tumours. Medulloblastoma is the most common brain cancer seen in young children. The main treatments available to children with medulloblastoma today are surgery, radiotherapy or chemotherapy. These treatments can be effective and kill the tumour cells in a proportion of patients; however they are almost invariably also causing severe side effects which are particularly damaging in young children as their brain is growing quickly. These side effects mainly affect a child's physical and intellectual development with hearing and visual disturbances, growth and hormonal changes, reduced fertility, behavioural changes, learning problems, difficulties with coordination and secondary cancers.

Importantly, recent experiments have revealed that medulloblastoma can be classified into different subgroups which predict their prognosis, including how they will respond to treatment. We have recently shown that a gene called BMI1 is strongly expressed in these tumours. We have observed that BMI1 is most strongly expressed in a subgroup of medulloblastoma that is associated with a particularly poor outcome.

We will take advantage of next generation sequencing techniques applied to a unique set of experimental model systems to explore the epigenetic regulation of medulloblastoma cells. Candidate genes and pathways identified in this screening will be robustly validated to assess their translational functional relevance (impact on the scientific community). As the selection criteria for identifying candidate genes from the genomic screening will be that they represent targetable pathways and/or carry prognostic value, their validation on human medulloblastoma datasets will directly lay the basis for high throughput drug screening to identify novel and more effective drugs against these currently lethal tumours (impact on patient health and pharma).

It is increasingly clear that interdisciplinary approaches are required to build upon our emerging understanding of brain cancer biology towards translation into new and improved treatments. There is currently a shortage of researchers with the requisite skills to cope with such an interdisciplinary approach to cancer research, hence there is a clear need to train young scientists to work and communicate effectively in this fast-changing, interdisciplinary research environment. This is a collaborative project between four research groups working on various aspects of cancer research, including experimental models of brain cancer, epigenetic regulation of gene expression, next generation genomics, advanced integrated bioinformatics platforms and molecular pathology. The postdoctoral fellow employed on this grant will have an excellent opportunity to train in these various aspects of brain cancer research and will develop essential skills to effectively interact with teams of scientists with diverse scientific background (impact on the scientific community and education).
The groups involved in this project meet regularly and the postdoctoral fellow will attend these meetings and actively present their data. Moreover, the post-doctoral fellow will attend and present at national and international conferences relating to brain tumour research (impact on the scientific community and education).
Within the Blizard Institute there are excellent opportunities to become involved in outreach activities, see public engagement section for details (impact on the general public).

Publications

10 25 50
 
Description APPG Brain Tumours
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description Cabinet Office Roundtable on a global strategy to support brain tumour research in the UK and abroad
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
 
Description Chair Scientific Advisory Board Children with Cancer UK
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
Impact I am the chair of a SAB which allocates funding to young medical postgraduate trainees to gain and refine skills in all aspects of childhood cancer.
 
Description MRC/Brain Tumour Research Workshop
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
 
Description Barts Charity - Programme Grant
Amount £1,500,000 (GBP)
Organisation Barts Charity 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2019 
End 12/2024
 
Description Brain Tumour Research Centre of Excellence
Amount £3,300,000 (GBP)
Organisation Brain Tumour Research 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2015 
End 12/2019
 
Description Clinical Research Training Fellowship for a neuropathology trainee
Amount £43,789 (GBP)
Organisation Mason Medical Research Foundation 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2015 
End 10/2016
 
Description MRC/BTC Clinical Research Training Fellowship to a neuropathology trainee (Marino Supervisor)
Amount £246,281 (GBP)
Organisation The Brain Tumour Charity 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2016 
End 09/2019
 
Title Culturing primary medulloblastoma cells 
Description Established methods to culture and maintain primary medulloblastoma cells, see Badodi et al 2018 
Type Of Material Cell line 
Year Produced 2018 
Provided To Others? Yes  
Impact Cells can be used for functional testing and drug screening. 
 
Title Transcriptomic datasets 
Description A first batch of datasets generated in the context of this project have been made publicly available, see Badodi et al. 2017 
Type Of Material Technology assay or reagent 
Year Produced 2017 
Provided To Others? Yes  
Impact Availability of datasets for comparative analysis. 
 
Description CRUK Multicentre Accelerator Award 
Organisation University College London
Department Institute of Neurology
Country United Kingdom 
Sector Academic/University 
PI Contribution I have contributed to the writing of the application as a named collaborator, I will contribute my clinical neuropathological knowledge and my scientific expertise in brain tumour biology to the consortium.
Collaborator Contribution I will gain access to tumour samples and cell lines generated and characterised through the consortium, my research team and I will attend research meetings and profit from the overall expertise and resources of the consortium. We will link to the bioinformatics hub to be established by the consortium.
Impact No output yet, collaboration just started.
Start Year 2016
 
Description Cancer evolution in syngeneic tumour/iNSC pairs 
Organisation Queen Mary University of London
Department Barts Cancer Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution Generation and characterisation of primary lines, generation of epigenomic datasets, contribution to design of experiments
Collaborator Contribution Knowledge on cancer evolution, computational modelling, contribution to design of experiments.
Impact Currently working on a grant proposal to be submitted to CRUK
Start Year 2018
 
Description Computational modelling and analysis of epigenetic datasets 
Organisation Uppsala University
Country Sweden 
Sector Academic/University 
PI Contribution Generation of unique epigenomic datasets for collaborative research, formulate research questions
Collaborator Contribution Bioinformatic analytical skills and computational modelling
Impact Multidisciplinary: bioinformatics, mathematical modelling, epigenomics, cellular and molecular biology
Start Year 2017
 
Description Correlation of epigenetic datasets with proteomic datasets 
Organisation Curie Institute Paris (Institut Curie)
Country France 
Sector Academic/University 
PI Contribution Original hypothesis to be tested, new epigenomics datasets.
Collaborator Contribution Published and unpublished proteomics datasets, computational correlation pipeline.
Impact Collaboration just started
Start Year 2019
 
Description High throughput drug screening 
Organisation Sanford-Burnham Medical Research Institute
Country United States 
Sector Charity/Non Profit 
PI Contribution Generated edited primary lines and controls for screening, formulated scientific questions and contributed to experimental screening plan
Collaborator Contribution High throughput compound screening expertise, designed experimental plan for deconvolution
Impact Collaboration just started, no output so far
Start Year 2017
 
Description Article for The Conversation (online) and printed in i Newspaper 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Written an article on clinical trials in near-oncology.
Year(s) Of Engagement Activity 2018
 
Description Laboratory Tour for the public 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Series of 6 Lab Tours per year: Guided laboratory visits, discussions of current research topics, demonstrations of research activities. Mentoring of junior lab members while taking part in public engagement activities.
Year(s) Of Engagement Activity 2015,2016,2017,2018
 
Description MRC/Brain Tumour Research Workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact The aim of the workshop was to identify crossdisciplinary research opportunities between neuroscience and brain tumour research. I have contributed to organising the workshop, moderated one session and given a talk.
Year(s) Of Engagement Activity 2018
 
Description Press release to disseminate research news to the wider public 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Press release on Niklison-Chirou et al G&D 2017 and Badodi et al. Cell Reports 2017
Year(s) Of Engagement Activity 2017
 
Description Tessa Jowell Brain Cencer Mission 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact To design the national brain tumour research and training strategy.
Year(s) Of Engagement Activity 2018
URL http://www.thebraintumourcharity.org/get-involved/campaigning-for-change/what-were-campaigning/tessa...
 
Description Various activities to raise awareness of brain tumour research 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact 4 Lab tours with ~20 attendees, attendance to parliamentary events organised by charities, attendance to fundraising events
Year(s) Of Engagement Activity 2015