Paediatric Strategy Forum for medicinal product development of epigenetic modifiers for children: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration

Andrew DJ Pearson, Kimberly Stegmaier, Franck Bourdeaut, Gregory Reaman, Delphine Heenen, Michael L. Meyers, Scott A. Armstrong, Patrick Brown, Daniel De Carvalho, Nada Jabado, Lynley Marshall, Miguel Rivera, Malcolm Smith, Peter C. Adamson, Amy Barone, Christian Baumann, Samuel Blackman, Vickie Buenger, Martha Donoghue, Aundrietta D. DuncanElizabeth Fox, Brian Gadbaw, Maureen Hattersley, Peter Ho, Ira Jacobs, Michael J. Kelly, Mark Kieran, Giovanni Lesa, Franca Ligas, Donna Ludwinski, Joe McDonough, Zariana Nikolova, Koen Norga, Adrian Senderowicz, Tilmann Taube, Susan Weiner, Dominik Karres, Gilles Vassal

Research output: Contribution to journalReview articlepeer-review

2 Scopus citations


The fifth multistakeholder Paediatric Strategy Forum focussed on epigenetic modifier therapies for children and adolescents with cancer. As most mutations in paediatric malignancies influence chromatin-associated proteins or transcription and paediatric cancers are driven by developmental gene expression programs, targeting epigenetic mechanisms is predicted to be a very important therapeutic approach in paediatric cancer. The Research to Accelerate Cures and Equity (RACE) for Children Act FDARA amendments to section 505B of the FD&C Act was implemented in August 2020, and as there are many epigenetic targets on the FDA Paediatric Molecular Targets List, clinical evaluation of epigenetic modifiers in paediatric cancers should be considered early in drug development. Companies are also required to submit to the EMA paediatric investigation plans aiming to ensure that the necessary data to support the authorisation of a medicine for children in EU are of high quality and ethically researched. The specific aims of the forum were i) to identify epigenetic targets or mechanisms of action associated with epigenetic modification relevant to paediatric cancers and ii) to define the landscape for paediatric drug development of epigenetic modifier therapies. DNA methyltransferase inhibitors/hypomethylating agents and histone deacetylase inhibitors were largely excluded from discussion as the aim was to discuss those targets for which therapeutic agents are currently in early paediatric and adult development. Epigenetics is an evolving field and could be highly relevant to many paediatric cancers; the biology is multifaceted and new targets are frequently emerging. Targeting epigenetic mechanisms in paediatric malignancy has in most circumstances yet to reach or extend beyond clinical proof of concept, as many targets do not yet have available investigational drugs developed. Eight classes of medicinal products were discussed and prioritised based on the existing level of science to support early evaluation in children: inhibitors of menin, DOT1L, EZH2, EED, BET, PRMT5 and LSD1 and a retinoic acid receptor alpha agonist. Menin inhibitors should be moved rapidly into paediatric development, in view of their biological rationale, strong preclinical activity and ability to fulfil an unmet clinical need. A combination approach is critical for successful utilisation of any epigenetic modifiers (e.g. EZH2 and EED) and exploration of the optimum combination(s) should be supported by preclinical research and, where possible, molecular biomarker validation in advance of clinical translation. A follow-up multistakeholder meeting focussing on BET inhibitors will be held to define how to prioritise the multiple compounds in clinical development that could be evaluated in children with cancer. As epigenetic modifiers are relatively early in development in paediatrics, there is a clear opportunity to shape the landscape of therapies targeting the epigenome in order that efficient and optimum plans for their evaluation in children and adolescents are developed in a timely manner.

Original languageEnglish (US)
Pages (from-to)135-148
Number of pages14
JournalEuropean Journal of Cancer
StatePublished - Nov 2020


  • Cancer therapeutics
  • Drug development
  • Epigenetic mechanisms
  • Paediatric oncology
  • Paediatric strategy forum

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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