Hot TopicThe role of the ‘innovative therapies for children with cancer’ (ITCC) European consortium
Section snippets
Cancer in children
Childhood cancer can be divided into three broad sub-categories: leukemias, brain tumors (including benign tumors) and extra-cranial solid tumors, each comprising approximately one-third of the total number of cases of childhood cancer. The histology is significantly different from that observed in adults. In leukemias, acute lymphoblastic leukemia (ALL) is approximately 5–6 times more common than acute myeloid leukemia (AML), and chronic leukemias are rare. In solid tumors, carcinomas are rare
Improvement of outcome
Currently, approximately 70% of children with cancer can be cured. This has been achieved by stepwise improvements through sequential treatment optimization studies. These studies have fine-tuned the scheduling of currently available chemotherapy and other treatment modalities such as surgery and radiotherapy. However, the improvements in cure rates seem to have slowed down during the past decade, probably because we have reached the level where it is difficult to further improve outcome with
Changes in legislation in Europe
Until a few years ago, there was limited interest from pharmaceutical industries in Europe for drug development studies in children. For instance, Hirschfeld et al. investigated more than 100 drugs that had been approved by the FDA for the treatment of malignancies.28 Only 15 had pediatric use information in their labeling, which was less than 50% of the drugs commonly used in the treatment of pediatric malignancies. On January 27th 2007, a new legislation governing the development and
Ethical aspects
The need to develop new medicines for children is unquestionable. The risk/benefit ratio always needs to be evaluated at the individual patient level, and fair understandable information must be provided to the parents and/or the child, in line with local rules and regulations. Younger children may not be able to provide informed consent, and hence additional protection for this vulnerable group of potential participants is needed. An important aspect is the potential therapeutic benefit for
Increasing numbers of sub-groups
Due to the increased understanding of the pathophysiology of many types of childhood cancer, there are many new sub-groups identified with targets that are only present in a small sub-group of patients of a specific disease. This further subdivides these rare diseases in even rarer sub-groups. An example is KIT-mutated AML, which may be targeted with tyrosine kinase inhibitors, but which occurs only in approximately 10% of pediatric AML cases.41 In order to target this mutation, a European
Conclusions
Five years after its initiation, ITCC is a viable and well-established organization to address the challenges of new drug development for children with cancer. Current efforts are directed towards being a legal organization with a consortium agreement between the centers, to further improve the collaboration and the capacity to collaborate with pharmaceutical companies. The objectives discussed in this chapter have not changed, and the goal for the next 5 years is to further expand the number of
Conflict of interest statement
ITCC is an academic consortium. It is not funded by or dependent on funding of the pharmaceutical industry. None of the authors have conflicts of interest including specific financial interests, relationships, and/or affiliations relevant to the subject matter included in this manuscript.
Acknowledgement
The authors like to thank all centers mentioned in Table 1 for actively contributing in the ITCC consortium, and all others who have contributed either by referring patients or otherwise for their collaboration with ITCC.
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Cited by (52)
Clinical research with targeted drugs in paediatric oncology
2023, Drug Discovery TodayPrecision medicine in pediatric solid cancers
2022, Seminars in Cancer BiologyCitation Excerpt :As discussed above, the genomic profiles of pediatric tumor entities differ from adult cancer with a lower overall mutational load [8], but nevertheless carry actionable gene fusions [211,212] and alterations in genes proven as predictive biomarkers in adult indications [211]. Frequently altered molecular pathways, including receptor tyrosine kinases (RTKs), the RAS-MAPK and the PI3K-AKT-mTOR signaling pathways, can be targeted by e.g. small molecule tyrosine kinase inhibitors [213–215]. Further drug classes include agents targeting epigenetic alterations, immune-checkpoint inhibitors, monocloncal antibodies [216–218] or tumor vaccination approaches [219–224] (see above).
Target actionability review to evaluate CDK4/6 as a therapeutic target in paediatric solid and brain tumours
2022, European Journal of CancerCitation Excerpt :This argues a strong case for the need to systematically review proof-of-concept (PoC) preclinical data to match paediatric tumour entities to the most promising therapeutic options. To address this, the target actionability review (TAR) methodology [6] was previously established as part of the innovative therapies for children with cancer paediatric preclinical PoC platform (ITCC-P4), an innovative medicines initiative 2-funded public–private partnership between academic research institutions and pharmaceutical companies [7]. In a pilot TAR evaluating the MDM2-TP53 pathway in primary tumour data and preclinical models of paediatric cancers, we demonstrated that the TAR methodology provided the most comprehensive overview of available preclinical data on targeting of MDM2 in paediatric cancer to date [6].
ACCELERATE – Five years accelerating cancer drug development for children and adolescents
2022, European Journal of CancerCitation Excerpt :This outcome is the result, as previously stated, of drug development being driven by the adult condition. Although the number of drugs in early phase clinical trials delivered by the Innovative Therapies for Children with Cancer Consortium (ITCC) [15] had increased from one in 2007 to 12 in 2013 (half being conducted to comply with regulatory requirement of PIPs), many children still lacked access to novel therapies at the time of relapse. Furthermore, there was still a lack of early access to new drugs for both preclinical and clinical trials.
Target Actionability Review: a systematic evaluation of replication stress as a therapeutic target for paediatric solid malignancies
2022, European Journal of CancerCitation Excerpt :Ad hoc administration of unapproved (in children) drugs undermines the ethical and systematic development of safe therapeutics for children with cancer and perpetuates the challenges explained previously. To help prioritise mechanism-of-action-based drugs for paediatric clinical development, a systematic literature review strategy was developed to summarise current knowledge into proof-of-concept (PoC) terms as part of the Innovative Therapies for Children with Cancer Paediatric Preclinical Proof-of-Concept Platform (ITCC-P4; Grant Agreement No 116064) [3,4]. Using this structured and stepwise workflow, our current target actionability review (TAR) evaluates the PoC preclinical data of published literature focused on targeting replication stress in 16 different paediatric intracranial and extracranial solid tumour types.
Combined targeting of the p53 and pRb pathway in neuroblastoma does not lead to synergistic responses
2021, European Journal of Cancer