Implementation of mechanism of action biology-driven early drug development for children with cancer

Abstract

An urgent need remains for new paediatric oncology drugs to cure children who die from cancer and to reduce drug-related sequelae in survivors. In 2007, the European Paediatric Regulation came into law requiring industry to create paediatric drug (all types of medicinal products) development programmes alongside those for adults. Unfortunately, paediatric drug development is still largely centred on adult conditions and not a mechanism of action (MoA)-based model, even though this would be more logical for childhood tumours as these have much fewer non-synonymous coding mutations than adult malignancies. Recent large-scale sequencing by International Genome Consortium and Paediatric Cancer Genome Project has further shown that the genetic and epigenetic repertoire of driver mutations in specific childhood malignancies differs from more common adult-type malignancies. To bring about much needed change, a Paediatric Platform, ACCELERATE, was proposed in 2013 by the Cancer Drug Development Forum, Innovative Therapies for Children with Cancer, the European Network for Cancer Research in Children and Adolescents and the European Society for Paediatric Oncology. The Platform, comprising multiple stakeholders in paediatric oncology, has three working groups, one with responsibility for promoting and developing high-quality MoA-informed paediatric drug development programmes, including specific measures for adolescents. Key is the establishment of a freely accessible aggregated database of paediatric biological tumour drug targets to be aligned with an aggregated pipeline of drugs. This will enable prioritisation and conduct of early phase clinical paediatric trials to evaluate these drugs against promising therapeutic targets and to generate clinical paediatric efficacy and safety data in an accelerated time frame. Through this work, the Platform seeks to ensure that potentially effective drugs, where the MoA is known and thought to be relevant to paediatric malignancies, are evaluated in early phase clinical trials, and that this approach to generate pre-clinical and clinical data is systematically pursued by academia, sponsors, industry, and regulatory bodies to bring new paediatric oncology drugs to front-line therapy more rapidly.

Outcome and prognostic factors in high‐risk childhood adrenocortical carcinomas: A report from the European Cooperative Study Group on Pediatric Rare Tumors (EXPeRT)

“…Moreover, as survival of metastatic patients is really poor, these patients should have the proposition to be included within prospective new drug protocols. 32 Finally, this study demonstrates that international cooperation and prospective cooperative protocols may expand our knowledge about these rare tumors and lead to collection of a more accurate data. 33…”

“…From our study results, we can prospectively select those patients who absolutely need perioperative medical therapies in order to improve the outcome (large tumors, metastatic spread, at least two risk factors). Moreover, as survival of metastatic patients is really poor, these patients should have the proposition to be included within prospective new drug protocols …”

Biological material collection to advance translational research and treatment of children with CNS tumours: position paper from the SIOPE Brain Tumour Group

“…To bring about muchneeded improvements regarding the availabilities of new drugs for children with brain tumours, paediatric platforms such as ACCELERATE have been proposed by the Cancer Drug Development Forum, Innovative Therapies for Children with Cancer, the European Network for Cancer Research in Children and Adolescents, and SIOPE. 76 These platforms aim to establish and improve paediatric drug-development programmes informed by mechanism-of-action know ledge, with aggregated databases of biological drug targets for paediatric tumours, to ultimately enable prioritisation and more rapid conduct of early-phase clinical trials for paediatric malignancies.…”

N-(2-hydroxyphenyl)-2-propylpentanamide, a valproic acid aryl derivative designed in silico with improved anti-proliferative activity in HeLa, rhabdomyosarcoma and breast cancer cells

“…Due to the great number of pediatric patients that die secondary to cancer disease and also, due to there are several unknown factors associated to these diseases, the European Pediatric Regulation has invited to develop drugs focused to pediatric population alongside to research programs for adults. However, there are several genetic and epigenetic factors that could represent an important genomic project to find a potential treatment or treatments in this kind of patients 6 . Histones are octameric proteins formed by dimers of 2A, 2B, 3 and 4 subunits.…”