Paediatric Strategy Forum for medicinal product development of DNA damage response pathway inhibitors in children and adolescents with cancer: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration

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Item Type:	Review
Title:	Paediatric Strategy Forum for medicinal product development of DNA damage response pathway inhibitors in children and adolescents with cancer: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration
Creators Name:	Pearson, A.D.J. and Federico, S. and Gatz, S.A. and Ortiz, M. and Lesa, G. and Scobie, N. and Gounaris, I. and Weiner, S.L. and Weigel, B. and Unger, T.J. and Stewart, E. and Smith, M. and Slotkin, E.K. and Reaman, G. and Pappo, A. and Nysom, K. and Norga, K. and McDonough, J. and Marshall, L.V. and Ludwinski, D. and Ligas, F. and Karres, D. and Kool, M. and Horner, T.J. and Henssen, A. and Heenen, D. and Hawkins, D.S. and Gore, L. and Bender, J.G. and Galluzzo, S. and Fox, E. and de Rojas, T. and Davies, B.R. and Chakrabarti, J. and Carmichael, J. and Bradford, D. and Blanc, P. and Bernardi, R. and Benchetrit, S. and Akindele, K. and Vassal, G.
Abstract:	DNA damage response inhibitors have a potentially important therapeutic role in paediatric cancers; however, their optimal use, including patient selection and combination strategy, remains unknown. Moreover, there is an imbalance between the number of drugs with diverse mechanisms of action and the limited number of paediatric patients available to be enrolled in early-phase trials, so prioritisation and a strategy are essential. While PARP inhibitors targeting homologous recombination-deficient tumours have been used primarily in the treatment of adult cancers with BRCA1/2 mutations, BRCA1/2 mutations occur infrequently in childhood tumours, and therefore, a specific response hypothesis is required. Combinations with targeted radiotherapy, ATR inhibitors, or antibody drug conjugates with DNA topoisomerase I inhibitor-related warheads warrant evaluation. Additional monotherapy trials of PARP inhibitors with the same mechanism of action are not recommended. PARP1-specific inhibitors and PARP inhibitors with very good central nervous system penetration also deserve evaluation. ATR, ATM, DNA-PK, CHK1, WEE1, DNA polymerase theta and PKMYT1 inhibitors are early in paediatric development. There should be an overall coordinated strategy for their development. Therefore, an academia/industry consensus of the relevant biomarkers will be established and a focused meeting on ATR inhibitors (as proof of principle) held. CHK1 inhibitors have demonstrated activity in desmoplastic small round cell tumours and have a potential role in the treatment of other paediatric malignancies, such as neuroblastoma and Ewing sarcoma. Access to CHK1 inhibitors for paediatric clinical trials is a high priority. The three key elements in evaluating these inhibitors in children are (1) innovative trial design (design driven by a clear hypothesis with the intent to further investigate responders and non-responders with detailed retrospective molecular analyses to generate a revised or new hypothesis); (2) biomarker selection and (3) rational combination therapy, which is limited by overlapping toxicity. To maximally benefit children with cancer, investigators should work collaboratively to learn the lessons from the past and apply them to future studies. Plans should be based on the relevant biology, with a focus on simultaneous and parallel research in preclinical and clinical settings, and an overall integrated and collaborative strategy.
Keywords:	Paediatric Oncology, DNA Damage Response, Inhibitors, Paediatric Strategy, Forum, Drug Development, Cancer Therapeutics, Combinations
Source:	European Journal of Cancer
ISSN:	0959-8049
Publisher:	Pergamon Press
Volume:	190
Page Range:	112950
Date:	September 2023
Official Publication:	https://doi.org/10.1016/j.ejca.2023.112950
PubMed:	View item in PubMed

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