About the Project
Medulloblastoma (MB) is the commonest malignant childhood brain tumour. Advances in standard upfront-treatments (surgical removal of tumour, radiotherapy and chemotherapy) have led to survival rates of approximately 70%. Our research has identified four consensus molecular subgroups (MBWNT, Wnt/wingless-activated; MBSHH, Sonic-hedgehog-activated; MBGroup3, Group3; and MBGroup4, Group4), with divergent second-generation subtypes, genomic characteristics, and clinical relevance. Importantly, MYC oncogene amplification in MBGroup3 (MBGroup3-MYC) conveys a dismal prognosis; patients typically progress, or relapse shortly after standard upfront-treatment and subsequently die of disease (<10% survival).
MBGroup3-MYC thus accounts for a high proportion of childhood cancer deaths, and is one of the most significant unmet clinical challenges in childhood cancer. This project aims to develop new therapies for MBGroup3-MYC using comprehensive disease modelling approaches. To date, we have developed three independent isogenic MBGroup3 cell-line models (iMBGroup3-MYC) with regulable MYC expression to investigate the role of MYC in drug resistance. High-throughput drug screening in these cell-line models has already identified promising new MYC-targeting drugs for further investigation.
This project will advance these early findings and will develop novel MBGroup3-MYC mouse models, then use these to test new MYC-targeting drugs and understand their mechanism(s) of action. The major objectives are:
I: To use integrated chemo-informatics approaches to prioritise MYC-targeting drugs identified from high-throughput screens in our iMBGroup3-MYC cell-line models.
II: To develop and characterise novel iMBGroup3-MYC mouse models with regulable MYC expression.
III: To establish new MBGroup3-MYC mouse models using patient-derived xenografts, to provide disease-relevant models which re-capitulate intra-tumoural heterogeneity, for further assessment of MYC-targeting drugs identified.
IV: To test and validate MYC-targeting drugs in our novel MBGroup3-MYC mouse models, including, efficacy, pharmacokinetic and pharmacodynamic studies, to identify best agents to advance into future clinical trials.
Training: You will be embedded within the Paediatric Brian Tumour Group (PBTG), Newcastle University Centre for Cancer (NUCC), which has an international reputation for translational research in medulloblastoma. We are a supportive, friendly, dynamic multi-disciplinary team comprising; basic and clinician scientists, bioinformaticians and statisticians. Together, we work with multiple international partners to improve survival, and the quality of survival, of childhood brain tumours. You will therefore have opportunities to interact with collaborating teams, for example, in Great Ormond Street Hospital, London, Telethon Kids Institute, Perth, and The German Cancer Research Centre, Heidelberg. You will receive training in; in vitro and in vivo techniques including the development of novel mouse models, analyses of drug screen and multi-omic datasets (for example RNA-seq) and pre-clinical animal trials.
Together we will provide you with all the necessary training and expertise to successfully complete your studentship. Furthermore, we are committed to student wellbeing and career development. You will receive support from our Graduate School and NUCC, including all training opportunities offered by these institutions. We also have an active PhD student cohort which meet regularly with the NUCC Postgraduate Programme Supervisor, and a highly-successful annual Postgraduate Research Conference. Together we will help you to develop your academic and engagement skills throughout your studies, and encourage you to prepare your discoveries for national/international conferences and high-impact journals.
Good luck with your application!
For more information:
The Discovery Medicine North Doctoral Training Partnership, is a diverse community of PhD students across the North of England, researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle & Sheffield) are internationally recognised as centres of research excellence & can offer you access to state-of the-art facilities for high impact research.
We are very proud of our student-centred ethos & committed to supporting students. We offer bespoke training in key skills sought after in early career researchers, & opportunities to broaden your career horizons in a wide range of sectors.
Funding by the MRC provides additional funding for research placements, international training, internships in science policy, science communication & beyond. See how current DiMeN students have benefited here
Studentships commence: 1st October 2021
Matheson EC, Thomas H, Case M, Blair H, Jackson RK, Masic D, Veal G, Halsey C, Newell DR, Vormoor J, Irving JAE. Glucocorticoids and selumetinib are highly synergistic in RAS pathway mutated childhood acute lymphoblastic leukemia through upregulation of BIM. Haematologica. (2019) 104(9): p1804-11. DOI: 10.3324/haematol.2017.185975.
Hill RM, Kuijper S, Lindsey JC, Petrie K, Schwalbe EC, Barker K, Boult JK, Williamson D, Ahmad Z, Hallsworth A, Ryan SL, Poon E, Robinson SP, Ruddle R, Raynaud FI, Howell L, Kwok C, Joshi A, Nicholson SL, Crosier S, Ellison DW, Wharton SB, Robson K, Michalski A, Hargrave D, Jacques TS, Pizer B, Bailey S, Swartling FJ, Weiss WA, Chesler L, Clifford SC. Combined MYC and P53 defects emerge at medulloblastoma relapse and define rapidly progressive, therapeutically targetable disease. Cancer Cell. (2015) 27(1):p. 72-84. DOI: 10.1016/j.ccell.2014.11.002
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