期刊
EUROPEAN JOURNAL OF CANCER
卷 136, 期 -, 页码 52-68出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.ejca.2020.05.010
关键词
Neuroblastoma; Drug development; Phase I; Preclinical testing; Clinical trials; MYCN; Epigenetics
类别
资金
- Oak Foundation
- Instituto de Salud Carlos III (Juan Rodes research fellowship) [JR15/00041]
- Alex's Lemonade Stand Foundation Center of Excellence grant
- FWO Vlaanderen (fund for scientific research Flanders) [12U4718N]
- Olivia Hendrickx Research Fund
- Kom op tegen kanker
- Stichting tegen kanker [2018-125]
- R35 grant: NCI [R35 CA 220500]
- Neuroblastoma UK
- Smile With Siddy
Only one class of targeted agents (anti-GD2 antibodies) has been incorporated into front-line therapy for neuroblastoma since the 1980s. The Neuroblastoma New Drug Development Strategy (NDDS) initiative commenced in 2012 to accelerate the development of new drugs for neuroblastoma. Advances have occurred, with eight of nine high-priority targets being evaluated in paediatric trials including anaplastic lymphoma kinase inhibitors being investigated in front-line, but significant challenges remain. This article reports the conclusions of the second NDDS forum, which expanded across the Atlantic to further develop the initiative. Pre-clinical and clinical data for 40 genetic targets and mechanisms of action were prioritised and drugs were identified for early-phase trials. Strategies to develop drugs targeting TERT, telomere maintenance, ATRX, alternative lengthening of telomeres (ALT), BRIP1 and RRM2 as well as direct targeting of MYCN are high priority and should be championed for drug discovery. Promising pre-clinical data suggest that targeting of ALT by ATM or PARP inhibition may be potential strategies. Drugs targeting CDK2/9, CDK7, ATR and telomere maintenance should enter paediatric clinical development rapidly. Optimising the response to anti-GD2 by combinations with chemotherapy, targeted agents and other immunological targets are crucial. Delivering this strategy in the face of small patient cohorts, genomically defined subpopulations and a large number of permutations of combination trials, demands even greater international collaboration. In conclusion, the NDDS provides an internationally agreed, biologically driven selection of prioritised genetic targets and drugs. Improvements in the strategy for conducting trials in neuroblastoma will accelerate bringing these new drugs more rapidly to front-line therapy. (C) 2020 Elsevier Ltd. All rights reserved.
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