Accelerating drug development for neuroblastoma - New Drug Development Strategy: an Innovative Therapies for Children with Cancer, European Network for Cancer Research in Children and Adolescents and International Society of Paediatric Oncology Europe Neuroblastoma project

ABSTRACT

Introduction: Neuroblastoma, the commonest paediatric extra-cranial tumour, remains a leading cause of death from cancer in children. There is an urgent need to develop new drugs to improve cure rates and reduce long-term toxicity and to incorporate molecularly targeted therapies into treatment. Many potential drugs are becoming available, but have to be prioritised for clinical trials due to the relatively small numbers of patients.

Areas covered: The current drug development model has been slow, associated with significant attrition, and few new drugs have been developed for neuroblastoma. The Neuroblastoma New Drug Development Strategy (NDDS) has: 1) established a group with expertise in drug development; 2) prioritised targets and drugs according to tumour biology (target expression, dependency, pre-clinical data; potential combinations; biomarkers), identifying as priority targets ALK, MEK, CDK4/6, MDM2, MYCN (druggable by BET bromodomain, aurora kinase, mTORC1/2) BIRC5 and checkpoint kinase 1; 3) promoted clinical trials with target-prioritised drugs. Drugs showing activity can be rapidly transitioned via parallel randomised trials into front-line studies.

Expert opinion: The Neuroblastoma NDDS is based on the premise that optimal drug development is reliant on knowledge of tumour biology and prioritisation. This approach will accelerate neuroblastoma drug development and other poor prognosis childhood malignancies.

KEYWORDS:

• Neuroblastoma
• drug development
• phase I
• preclinical testing
• clinical trials

Article highlights

• The NDDS Project has initiated collaboration between clinicians, scientists and regulators

• The aim is to accelerate drug development for neuroblastoma

• Targets for neuroblastoma are prioritised according to tumour biology

• Prioritised targets include ALK, MEK, CDK4/6, MDM2, MYCN (druggable by BET bromodomain, aurora kinase and mTORC1/2 inhibition), BIRC5 and checkpoint Kinase 1

• Drugs targeting these pathways should be prioritized for early clinical trials

• Drugs that show promise in early phase trials should be evaluated in parallel randomized or multi-arm, multi-stage studies, and then into front-line studies - a three stage process from first in child studies to front-line therapy.

This box summarizes key points contained in the article.

Acknowledgments

The views expressed in this article are the personal views of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the European Medicines Agency or one of its committees or working parties. We thank Maren White for editorial assistance.

Declaration of interest

Lucas Moreno has participated in advisory boards for Novartis, AstraZeneca, Roche Genentech, MundiPharma, Bayer and Amgen. T Van Maerken has participated in advisory boards for Roche (Genentech) and has received RG7388 from Roche (Genentech) for preclinical testing in neuroblastoma. H Caron is an employee of Hoffman-La Roche. No other conflicts of interest to disclose. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Writing and editorial assistance was utilized in the production of this manuscript and funded by the research Fund of the CNIO-HNJ Clinical Research Unit, Madrid.

Additional information

Funding

Lucas Moreno was funded by the Oak Foundation and Instituto de Salud Carlos III (Rio Hortega and Juan Rodes research fellowships). Lynley Marshall was funded by the Oak Foundation while Andrew DJ Pearson was funded by Cancer Research UK (Programme Grant C1178/A10294—Chair in Pediatric Oncology). Editorial assistance was funded by the research Fund of the CNIO-HNJ Clinical Research Unit, Madrid.