Anticipatory medicine: Can we identify, predict, and target mechanisms of disease relapse in childhood medulloblastoma?

Lead Research Organisation: Newcastle University
Department Name: Northern Institute for Cancer Research

Abstract

Medulloblastoma is the most common malignant brain tumour of childhood. Approximately 80 children are diagnosed with the disease every year in the UK, and over 600 children across Europe per annum. Over the last 50 years, advances in treatment (surgical removal of tumour, radiotherapy and chemotherapy) have led to long-term survival rates of approximately 70%. Recently the scientific community has begun to understand the biology of medulloblastoma tumours at diagnosis and how this relates to clinical features and patient survival. Despite these discoveries however, survival rates have plateaued and remain at 70%.

Unfortunately, medulloblastoma comes back (disease relapse), in 30% of patients and is usually fatal, accounting for a very high proportion (10%) of childhood cancer deaths overall. Despite this clear unmet clinical need, the biology driving disease relapse has not been fully investigated, and there have been very few clinical trials aimed at treating children with relapsed medulloblastoma. This is likely due to the challenges of obtaining a tissue biopsy when the tumour returns, and the relative rarity of medulloblastoma relapse. However, a small number of key studies, undertaken by myself and others, have shown that tumour biology changes when a medulloblastoma tumour relapses. Until we understand the factors driving this changing biology and subsequent tumour return, the number of children dying from a relapsed medulloblastoma will remain the same.

This proposal will investigate the biology of medulloblastoma tumours sampled at relapse, and compare these findings to the biology of tumours sampled from the same patient at diagnosis. This will be achieved through the detailed investigation of an unprecedented collection of matched medulloblastoma tumour pairs. This cohort will be used to identify common and emerging biological factors, also known as genetic candidates, which are likely responsible for driving disease relapse. To investigate these genetic candidates, this Fellowship will use established, and new, medulloblastoma modelling systems which are derived from human tumour cells and therefore best represent the cell-to-cell variation observed in the disease. Medulloblastoma tumour cells will be grown in cell culture and in immunocompromised mice. These approaches have been designed to ensure experimental success, and will enable the direct assessment of genetic candidates to establish their role in relapsed disease biology. Drugs which target the most promising genetic candidates will be taken forward into pre-clinical drug trials in cell cultures and immunocompromised mice using the patient-derived models developed.

These original experiments will advance our understanding of medulloblastoma biology at relapse and, in the future, enable us to offer life-prolonging treatment to children whose tumour returns. These findings will also enable us to develop treatments to be used at diagnosis, which have the potential to prevent disease relapse and improve overall survival. Furthermore, changing biology between diagnosis and relapse is seen in a variety of other cancers. Therefore, the approaches developed in this proposal could be applied to other childhood brain tumours. In summary, understanding the factors which drive medulloblastoma relapse provides real hope that these factors are predictable, therapeutically targetable and can therefore be exploited to improve cure rates.

Technical Summary

Medulloblastoma is the most common malignant childhood brain tumour. Despite multimodal upfront therapy, relapse occurs in 30%, and is fatal in the majority. Pioneering studies by myself and others, have indicated that the molecular characteristics of relapse disease evolve over time, raising the hypothesis that the mechanism of relapse is predictable and targetable therapeutically. However, comprehensive characterisation of the molecular landscape of relapsed medulloblastoma has never been undertaken; consequently, the mechanisms driving relapse are not understood.

I have undertaken multi-omic profiling of >100 relapsed medulloblastomas and their paired diagnostic counterparts. Individual and integrative analyses of these datasets will identify candidate driver events enriched at relapse and supported by multiple strands of evidence. These will be taken forward for functional assessment. Focused in vitro and in vivo RNAi screens will be performed in established, disease-matched transgenic and novel patient-derived models, to assess candidates' roles in pathogenesis. Competitive co-culture and transplantation approaches in patient-derived models will be utilised to validate prime candidates.

This proposal will deliver key translational advances by identifying, prioritising and characterising targets associated with relapse, and by developing a repertoire of patient-derived models for target interrogation and developmental therapeutics. Targets will be pursued pre-clinically though repurposing approaches in these models where established target-drug combinations exist, and in collaboration with the Newcastle Drug Discovery Unit for novel targets. These approaches will provide the essential evidence required to support early-phase trials. Furthermore, these discoveries will uncover the potential to change upfront-treatment, whereby we can anticipate and target the drivers of relapse at diagnosis, aimed at preventing relapse and improving disease outcomes.

Planned Impact

This Fellowship will develop a greater understanding of the mechanisms driving relapsed medulloblastoma, and provides the foundation for new approaches in the treatment of medulloblastoma.

Patients, families and health services: The immediate beneficiaries will be children and their families coping with the diagnosis of medulloblastoma. The discovery of therapeutic targets and conception of an early-phase trial in relapsed medulloblastoma is a major long-term aim (within 5 years of Fellowship completion). At relapse, patients will benefit from agents that are potentially life-prolonging and, in rare cases, life-saving when applied in conjunction with established treatment modalities. Therapies employed in the upfront setting will be utilised to prevent relapse through the suppression of tumour evolution. These approaches have potential to impact overall survival rates, prolong quality of life after relapse, improve quality of upfront survivorship, and reduce the burden of care. Furthermore, aligned with the National Cancer Survivorship Initiative, upfront anticipatory treatments have potential to reduce standard-treatment and minimise the burden of long-term toxicities. This in turn will have long-term cost benefit implications for Primary Care Services and the NHS.

Commercial benefit: This proposal has long-term (5-10 years) commercial potential through the development of patient-derived models, tumorigenicity screens, and novel target discovery. Importantly all of these future outputs have potential utility across multiple paediatric tumour types. Reciprocal agreements for the sharing of patient-derived models with collaborators at other research institutions (e.g. DKFZ) are anticipated to expand throughout this Fellowship (e.g. Princess Máxima Center Utrecht). Furthermore, to engage with the global academic audience, industrial collaborations and commercialisation of patient-derived models will also be explored. Development of novel therapies will be undertaken with the CRUK-Newcastle Drug Discovery Unit and appropriate pharmaceutical partnerships.

Precision medicine and capacity development: My proposal is in line with global demand for precision medicine, an initiative evident nationally in paediatric oncology with the integration of whole genome sequencing into standard diagnostic testing, and molecular profiling of relapsed paediatric tumours (SMPaeds). These advancements also align with the Royal College of Paediatrics and Child Health recommendation for the expansion of clinical academic paediatricians. Development of my skills and knowledge will enable me to integrate multi-omic molecular data into routine clinical practice on a daily basis. These integrated skills will benefit patients, the local Paediatric Oncology department, and will further raise the profile of the Great North Children's Hospital and NUCC as leaders in paediatric oncology research.

My integrated up-to-date knowledge will benefit any future clinical or academic trainee that I supervise, and contribute to teaching excellence within Newcastle University. This Fellowship will also be instrumental in developing the affiliated post-doctoral position and my own research team. Team members will have; the opportunity to develop expertise in a variety of skills, exposure to leading international research groups, and the ability to contribute to the wider paediatric oncology community. Importantly I am embedded within the CCLG Neuro-Oncology Special Interest Group, Embryonal Brain Tumour Group and SIOPE Brain Tumour Group (co-chair of SIOPE Relapsed Medulloblastoma Working Group). I will develop these key roles and my own skills so that upon completion of this Fellowship I will be poised to translate discoveries Europe-wide, maximising patient benefit, strengthening international relationships for future collaborations, and providing a blueprint for equivalent strategies in other high-risk brain tumours.

Publications

10 25 50
 
Description Relapsed Medulloblastoma in Pre-Irradiated Patients: Current Practice for Diagnostics and Treatment
Geographic Reach Multiple continents/international 
Policy Influence Type Contribution to new or Improved professional practice
URL https://pubmed.ncbi.nlm.nih.gov/35008290/
 
Description Advancing novel treatment strategies for MYC-amplified medulloblastoma, one of the most fatal brain tumours of childhood
Amount £15,000 (GBP)
Funding ID 2601994 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 08/2021 
End 03/2025
 
Description Developing and delivering small molecule drug and immunotherapy combinations for MYC-driven medulloblastoma: Efficacy, evolution and exploitation.
Amount £1,053,350 (GBP)
Organisation Little Princess Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2022 
End 01/2026
 
Description INSTINCT-MB: Strategic implementation of novel combination therapeutics for high-risk medulloblastoma
Amount £1,774,158 (GBP)
Organisation Children with Cancer UK 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2022 
End 01/2027
 
Description Australia collaboration 
Organisation Telethon Kids Institute
Country Australia 
Sector Charity/Non Profit 
PI Contribution Molecular interrogation of medulloblastoma tumours sampled at both diagnosis and relapse.
Collaborator Contribution Provision of tumour samples to increase cohort size.
Impact See publication section: Richardson S, Hill RM, Kui C, Lindsey JC, Grabovksa Y, Keeling C..... Clifford SC, (2022). Emergence and maintenance of actionable genetic drivers at medulloblastoma relapse.. Neuro-oncology, 24 (1), pp. 153-165 Hill R, Richardson S, Schwalbe E, Hicks D, Lindsey J, Crosier S..... Clifford S, (2020). Time, pattern, and outcome of medulloblastoma relapse and their association with tumour biology at diagnosis and therapy: a multicentre cohort study. The Lancet Child & Adolescent Health.
Start Year 2014
 
Description Australia collaboration 
Organisation The Children's Hospital at Westmead
Country Australia 
Sector Hospitals 
PI Contribution Molecular interrogation of medulloblastoma tumours sampled at both diagnosis and relapse.
Collaborator Contribution Provision of tumour samples.
Impact See publication section: Richardson S, Hill RM, Kui C, Lindsey JC, Grabovksa Y, Keeling C..... Clifford SC, (2022). Emergence and maintenance of actionable genetic drivers at medulloblastoma relapse.. Neuro-oncology, 24 (1), pp. 153-165 Hill R, Richardson S, Schwalbe E, Hicks D, Lindsey J, Crosier S..... Clifford S, (2020). Time, pattern, and outcome of medulloblastoma relapse and their association with tumour biology at diagnosis and therapy: a multicentre cohort study. The Lancet Child & Adolescent Health.
Start Year 2014
 
Description Children's Cancer and Leukemia Group (CCLG) 
Organisation Children's Cancer and Leukaemia Group (CCLG)
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Molecular interrogation of medulloblastoma samples taken at both diagnosis and relapse.
Collaborator Contribution Provision of medulloblastoma tumour samples and neuropathological review of tumour samples.
Impact Publications Combined MYC and TP53 defects emerge at medulloblastoma relapse and define rapidly progressive, therapeutically targetable disease. (For full details see publication section.) Emergence and maintenance of actionable genetic drivers at medulloblastoma relapse. (For full details see publication section.) Time, pattern, and outcome of medulloblastoma relapse and their association with tumour biology at diagnosis and therapy: a multicentre cohort study. (For full details see publication section.) Histologically defined central nervous system primitive neuro-ectodermal tumours (CNS-PNETS) display heterogeneous DNA methylation profiles and show relationships to other paediatric brain tumour types. (For full details see publication section.) Subgroup-specific prognostic implications of TP53 mutation in Medulloblastoma. (For full details see publication section.) TP53 mutations in favourable risk WNT subtype medulloblastoma. (For full details see publication section.) Presentations Combined MYC and TP53 defects emerge at medulloblastoma relapse and define rapidly progressive, therapeutically targetable disease. Hill RM et al. Poster presentation at the 10th NCRI Cancer Conference, November 2014. MYC and TP53 defects emerge and interact at medulloblastoma relapse, define rapidly progressive disease and can be targeted therapeutically. Hill RM et al. Oral presentation at the ISPNO, June 2014. MYC and TP53 defects interact at medulloblastoma relapse to define rapidly progressive disease and can be targeted therapeutically. Hill RM et al. Poster presentation at the AACR Annual Meeting, April 2014. Evaluation of multiplex ligation-dependent probe amplification (MLPA) as a method for detection of MYC/MYCN oncogene amplification in medulloblastoma. Hill RM et al. Poster presentation ISPNO, June 2012. TP53 mutations in favourable risk WNT subtype medulloblastoma. Hill RM et al. Poster presentation AACR Annual Meeting, April 2011.
Start Year 2010
 
Description European Society for Paediatric Oncology (SIOPE) 
Organisation European Society of Paediatric Oncology (SIOPE)
Country Belgium 
Sector Charity/Non Profit 
PI Contribution Co-chair of relapsed medulloblastoma working group, joint development of strategy for the treatment of relapsed medulloblastoma including; development of core working group membership, joint European Treatment Guidelines (publication) and future development of an early-phase trial.
Collaborator Contribution Joint development of strategy for the treatment of relapsed medulloblastoma including; development of core working group membership, joint European Treatment Guidelines (publication) and future development of an early-phase trial.
Impact See publication section: Hill R, Plasschaert S, Timmermann B, Dufour C, Aquilina K, Avula S, Donovan L... Fleischhack G. (2021). Relapsed Medulloblastoma in Pre-Irradiated Patients: Current Practice for Diagnostics and Treatment. Cancers,
Start Year 2019
 
Description INSTINCT Network 
Organisation Institute of Cancer Research UK
Country United Kingdom 
Sector Academic/University 
PI Contribution Sharing of technologies, techniques and samples.
Collaborator Contribution Sharing of technologies, techniques and samples.
Impact The INSTINCT programme integrates research programmes at three of the UK's leading paediatric brain tumour research centres - the Northern Institute for Cancer Research at Newcastle University, the UCL Institute of Child Health and the Institute of Cancer Research. See publication section: Grabovska Y, Mackay A, O'Hare P, Crosier S, Finetti M, Schwalbe E..... Williamson D, (2020). Pediatric pan-central nervous system tumor analysis of immune-cell infiltration identifies correlates of antitumor immunity.. Nature communications, 11 (1), pp. 4324 Pickles J, Fairchild A, Stone T, Brownlee L, Merve A, Yasin S..... Jacques T, (2020). DNA methylation-based profiling for paediatric CNS tumour diagnosis and treatment: a population-based study. The Lancet Child & Adolescent Health, Izquierdo E, Yuan L, George S, Hubank M, Jones C, Proszek P..... De Castro DG, (2017). Development of a targeted sequencing approach to identify prognostic, predictive and diagnostic markers in paediatric solid tumours.. Oncotarget, 8 (67), pp. 112036-112050 Hill R M, Kuijper S;Lindsey J C;Schwalbe E;Barker K;Boult J K R;Williamson D;Ahmad Z;Hallsworth A;Ryan S L;Poon E;Robinson S P;Ruddle R;Raynaud F I;Howell L;Kwok C;Joshi A;Leigh Nicholson S;Crosier S;Wharton S B;Robson K;Michalski A;Hargrave D;Jacques T S;Pizer B;Bailey S;Swartling F J;Petrie K;Weiss W A;Chesler L;Clifford S C. (2014). Combined MYC and TP53 defects emerge at medulloblastoma relapse and define rapidly progressive, therapeutically targetable disease.
Start Year 2016
 
Description INSTINCT Network 
Organisation University College London
Department Great Ormond Street Institute of Child Health
Country United Kingdom 
Sector Public 
PI Contribution Sharing of technologies, techniques and samples.
Collaborator Contribution Sharing of technologies, techniques and samples.
Impact The INSTINCT programme integrates research programmes at three of the UK's leading paediatric brain tumour research centres - the Northern Institute for Cancer Research at Newcastle University, the UCL Institute of Child Health and the Institute of Cancer Research. See publication section: Grabovska Y, Mackay A, O'Hare P, Crosier S, Finetti M, Schwalbe E..... Williamson D, (2020). Pediatric pan-central nervous system tumor analysis of immune-cell infiltration identifies correlates of antitumor immunity.. Nature communications, 11 (1), pp. 4324 Pickles J, Fairchild A, Stone T, Brownlee L, Merve A, Yasin S..... Jacques T, (2020). DNA methylation-based profiling for paediatric CNS tumour diagnosis and treatment: a population-based study. The Lancet Child & Adolescent Health, Izquierdo E, Yuan L, George S, Hubank M, Jones C, Proszek P..... De Castro DG, (2017). Development of a targeted sequencing approach to identify prognostic, predictive and diagnostic markers in paediatric solid tumours.. Oncotarget, 8 (67), pp. 112036-112050 Hill R M, Kuijper S;Lindsey J C;Schwalbe E;Barker K;Boult J K R;Williamson D;Ahmad Z;Hallsworth A;Ryan S L;Poon E;Robinson S P;Ruddle R;Raynaud F I;Howell L;Kwok C;Joshi A;Leigh Nicholson S;Crosier S;Wharton S B;Robson K;Michalski A;Hargrave D;Jacques T S;Pizer B;Bailey S;Swartling F J;Petrie K;Weiss W A;Chesler L;Clifford S C. (2014). Combined MYC and TP53 defects emerge at medulloblastoma relapse and define rapidly progressive, therapeutically targetable disease.
Start Year 2016
 
Description INSTINCT-MB 
Organisation Institute of Cancer Research UK
Country United Kingdom 
Sector Academic/University 
PI Contribution Joint development of three grant applications focused on developing and delivering small molecule drug and immunotherapy combinations for MYC-driven medulloblastoma. All three grant applications were successful to Fight Kids Cancer, Children with Cancer and Little Princess Trust grossing over £2M in research funds.
Collaborator Contribution Joint development of three grant applications focused on developing and delivering small molecule drug and immunotherapy combinations for MYC-driven medulloblastoma. All three grant applications were successful to Fight Kids Cancer, Children with Cancer and Little Princess Trust grossing over £2M in research funds.
Impact NA
Start Year 2021
 
Description INSTINCT-MB 
Organisation University College London
Department Great Ormond Street Institute of Child Health
Country United Kingdom 
Sector Public 
PI Contribution Joint development of three grant applications focused on developing and delivering small molecule drug and immunotherapy combinations for MYC-driven medulloblastoma. All three grant applications were successful to Fight Kids Cancer, Children with Cancer and Little Princess Trust grossing over £2M in research funds.
Collaborator Contribution Joint development of three grant applications focused on developing and delivering small molecule drug and immunotherapy combinations for MYC-driven medulloblastoma. All three grant applications were successful to Fight Kids Cancer, Children with Cancer and Little Princess Trust grossing over £2M in research funds.
Impact NA
Start Year 2021
 
Description ITCC Brain Tumour Committee 
Organisation Innovative Therapies for Children with Cancer (ITCC) Consortium
Country European Union (EU) 
Sector Public 
PI Contribution The ITCC Brain Committee steers the ITCC research program for children and adolescents with brain tumours. This multi-disciplinary committee has recently formed and has had two meetings. These were interactive meetings setting out goals and future areas for development with contributions at present by myself and collaborators being to participate in these discussions.
Collaborator Contribution The ITCC Brain Committee steers the ITCC research program for children and adolescents with brain tumours. This multi-disciplinary committee has recently formed and has had two meetings. These were interactive meetings setting out goals and future areas for development with contributions at present by myself and collaborators being to participate in these discussions.
Impact NA
Start Year 2021
 
Description Telethon Kids Institute 
Organisation Telethon Kids Institute
Country Australia 
Sector Charity/Non Profit 
PI Contribution Reciprocal MTA for the transfer of serial engrafted/established patient derived brain tumour xenografts alongside the sharing of expertise, trouble shooting, and techniques.
Collaborator Contribution Reciprocal MTA for the transfer of serial engrafted/established patient derived brain tumour xenografts alongside the sharing of expertise, trouble shooting, and techniques.
Impact No outputs yet
Start Year 2020
 
Description The Hospital for Sick Children, Toronto 
Organisation The Hospital for Sick Children (SickKids)
Country Canada 
Sector Hospitals 
PI Contribution Analysis of combined Illumina 450K methylation array dataset which consist of medulloblastoma samples taken at both diagnosis and relapse.
Collaborator Contribution Sharing of a Illumina 450K methylation array dataset which consistent of a cohort of matched medulloblastoma samples taken at both diagnosis and relapse.
Impact See publications section: Richardson S, Hill RM, Kui C, Lindsey JC, Grabovksa Y, Keeling C..... Clifford SC, (2022). Emergence and maintenance of actionable genetic drivers at medulloblastoma relapse.. Neuro-oncology, 24 (1), pp. 153-165 Hill R, Richardson S, Schwalbe E, Hicks D, Lindsey J, Crosier S..... Clifford S, (2020). Time, pattern, and outcome of medulloblastoma relapse and their association with tumour biology at diagnosis and therapy: a multicentre cohort study. The Lancet Child & Adolescent Health
Start Year 2015
 
Description Uppsala Univeristy 
Organisation Uppsala University
Country Sweden 
Sector Academic/University 
PI Contribution Sharing of DNA methylation data from human samples of paired diagnostic and relapsed medulloblastoma tumours.
Collaborator Contribution Agreements in place to share tumour material derived from GEMM MYC and MYCN driven models of medulloblastoma including viable cells lines for future experimental work.
Impact NA
Start Year 2019
 
Description Invited speaker Newcastle University NeuroSoc Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Undergraduate students
Results and Impact Invited talk entitled: Relapsed medulloblastoma, the past, present and future.
Year(s) Of Engagement Activity 2021
 
Description Invited speaker Newcastle University Translational and Clinical research Institute 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Other audiences
Results and Impact Delivery of a talk entitled: Relapsed medulloblastoma: from clinical frustration to clinical discovery
Year(s) Of Engagement Activity 2021