Abstract MB-013: MYC and TP53 defects interact at medulloblastoma relapse to define rapidly progressive disease and can be targeted therapeutically.
Hill, Rebecca M, Kuijper, Sanne, Lindsey, Janet C, Petrie, Kevin, Schwalbe, Ed C, Barker, Karen, Boult, Jessica K R, Williamson, Daniel, Ahmad, Zai, Hallsworth, Albert, Ryan, Sarra L, Poon, Evon, Robinson, Simon P, Ruddle, Ruth, Raynaud, Florence I, Howell, Louise, Kwok, Colin, Joshi, Abhijit, Nicholson, Sarah Leigh, Crosier, Stephen, Wharton, Stephen B, Robson, Keith, Michalski, Antony, Hargrave, Darren, Jacques, Thomas S, Pizer, Barry, Bailey, Simon, Swartling, Fredrik J, Weiss, William A, Chesler, Louis and Clifford, Steven C
(2014)
Abstract MB-013: MYC and TP53 defects interact at medulloblastoma relapse to define rapidly progressive disease and can be targeted therapeutically.
Neuro-Oncology, 16 (Sup 1).
i74-i74.
ISSN 1522-8517
Abstract
Relapse following multi-modal therapy is the most adverse event in medul- loblastoma. Currently .90% of relapsing patients die, accounting for ~10% of childhood cancer deaths. Medulloblastoma is heterogeneous at diagnosis, comprising four molecular subgroups with distinct clinicopathological and molecular features. The relevance of these features at relapse is unknown, making characterisation, modelling and targeted therapy of relapse biology essential to improve outcomes. We undertook a comprehensive investigation of the molecular and clinicopathological features of 29 relapsed medulloblastomas and paired tumour samples taken at diagnosis, including the assessment of features with established significance at diagnosis (e.g. TP53 pathway status, MYC/MYCN amplification and molecular subgroup status). Molecular subgroup was unchanged, however evidence of alteration of all other features examined was found at relapse, with the majority of changes (30/44) representing acquired high-risk events. Most notably, MYC gene family amplifications and TP53 pathway defects commonly emerged in combination at relapse following conventional multimodal treatment (P 1⁄4 0.02, 7/ 22, 32%) and predicted rapid progression to death (P 1⁄4 0.016). Spontaneous development of Trp53 inactivating mutations was similarly common in a transgenic model of MYCN driven medulloblastoma (GTML;Glt1-tTA/ TRE-MYCN-Luc). Direct modelling of this interaction in GTML/Trp53KI/KI mice enhanced medulloblastoma formation (100%, 43/43 vs. 6%, 3/50 in GTML; P , 0.0001), mimicked clinicopathological characteristics of TP53-MYC relapsed human tumours, and validated the role of TP53 in potentiating the growth of MYCN-driven medulloblastoma. Therapeutic inhibition of Aurora-A kinase using MLN8237 in these tumours, and in derived neurospheres in vitro, promoted degradation of MYCN, reduced tumour growth and prolonged survival. In summary, medulloblastomas display altered molecular, pathological and clinical features at relapse and the emergence of combined TP53-MYC gene family defects is common following conventional therapy. Their association with rapid demise, and their validation as driving and therapeutically exploitable events in a novel mouse model, strongly support routine biopsy at relapse to drive future therapeutic strategies.
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Uncontrolled Keywords: chemotherapy, regimen, child, medulloblastoma, diagnosis, neoplasms |
Depositing User:
Kevin Petrie
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Date Deposited: 22 Mar 2023 15:51 |
Last Modified: 22 Mar 2023 15:51 |
Contributors
Author: |
Kevin Petrie
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Author: |
Rebecca M Hill
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Author: |
Sanne Kuijper
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Janet C Lindsey
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Ed C Schwalbe
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Karen Barker
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Jessica K R Boult
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Daniel Williamson
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Author: |
Zai Ahmad
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Author: |
Albert Hallsworth
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Author: |
Sarra L Ryan
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Evon Poon
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Simon P Robinson
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Ruth Ruddle
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Florence I Raynaud
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Author: |
Louise Howell
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Colin Kwok
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Abhijit Joshi
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Sarah Leigh Nicholson
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Stephen Crosier
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Stephen B Wharton
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Author: |
Keith Robson
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Author: |
Antony Michalski
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Author: |
Darren Hargrave
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Author: |
Thomas S Jacques
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Author: |
Barry Pizer
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Author: |
Simon Bailey
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Author: |
Fredrik J Swartling
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Author: |
William A Weiss
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Author: |
Louis Chesler
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Author: |
Steven C Clifford
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