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Target actionability review to evaluate CDK4/6 as a therapeutic target in paediatric solid and brain tumours
Nil A Schubert1, Celine Y Chen2, Ana Rodríguez3
1Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
Background:
Childhood cancer is still a leading cause of death around the world. To improve outcomes, there is an urgent need for tailored treatment. The systematic evaluation of existing preclinical data can provide an overview of what is known and identify gaps in the current knowledge. Here, we applied the target actionability review (TAR) methodology to assess the strength and weaknesses of available scientific literature on CDK4/6 as a therapeutic target in paediatric solid and brain tumours by structured critical appraisal.
Methods:
Using relevant search terms in PubMed, a list of original publications investigating CDK4/6 in paediatric solid tumour types was identified based on relevancy criteria. Each publication was annotated for the tumour type and categorised into separate proof-of-concept (PoC) data modules. Based on rubrics, quality and experimental outcomes were scored independently by two reviewers. A third reviewer evaluated and adjudicated score discrepancies. Scores for each PoC module were averaged for each tumour type and visualised in a heatmap matrix in the publicly available R2 data portal.
Results And Conclusions:
This CDK4/6 TAR, generated by analysis of 151 data entries from 71 publications, showed frequent genomic aberrations of CDK4/6 in rhabdomyosarcoma, osteosarcoma, high-grade glioma, medulloblastoma, and neuroblastoma. However, a clear correlation between CDK4/6 aberrations and compound efficacy is not coming forth from the literature. Our analysis indicates that several paediatric indications would need (further) preclinical evaluation to allow for better recommendations, especially regarding the dependence of tumours on CDK4/6, predictive biomarkers, resistance mechanisms, and combination strategies. Nevertheless, our TAR heatmap provides support for the relevance of CDK4/6 inhibition in Ewing sarcoma, medulloblastoma, malignant peripheral nerve sheath tumour and to a lesser extent neuroblastoma, rhabdomyosarcoma, rhabdoid tumour and high-grade glioma. The interactive heatmap is accessible through R2 [r2platform.com/TAR/CDK4_6].
Insights
This study reviewed preclinical data on CDK4/6 inhibitors for childhood cancers. While CDK4/6 alterations are common, their direct link to treatment effectiveness needs more research, though some pediatric tumors show promise.
Area of Science:
- Oncology
- Pharmacology
- Genomics
Background:
- Childhood cancer remains a significant global health challenge, necessitating personalized treatment strategies.
- Systematic evaluation of preclinical data is crucial for identifying knowledge gaps and improving therapeutic outcomes.
- Cyclin-dependent kinase 4 and 6 (CDK4/6) are emerging as potential therapeutic targets in pediatric malignancies.
Purpose of the Study:
- To systematically evaluate the existing preclinical evidence for CDK4/6 inhibitors in pediatric solid and brain tumors.
- To assess the strength and limitations of current scientific literature regarding CDK4/6 as a therapeutic target.
- To identify specific pediatric tumor types where CDK4/6 inhibition shows promise or requires further investigation.
Main Methods:
- A Target Actionability Review (TAR) methodology was employed for structured critical appraisal of scientific literature.
- A comprehensive literature search was conducted in PubMed to identify relevant publications on CDK4/6 in pediatric solid tumors.
- Data from 71 publications (151 data entries) were analyzed, scored for quality and outcomes, and visualized in a heatmap.
Main Results:
- Frequent genomic aberrations of CDK4/6 were observed in rhabdomyosarcoma, osteosarcoma, high-grade glioma, medulloblastoma, and neuroblastoma.
- A direct correlation between CDK4/6 aberrations and compound efficacy was not consistently established across all evaluated tumor types.
- The analysis identified a need for further preclinical research on tumor dependence, predictive biomarkers, resistance mechanisms, and combination strategies for several pediatric indications.
Conclusions:
- CDK4/6 inhibition is supported as a relevant therapeutic strategy for Ewing sarcoma, medulloblastoma, malignant peripheral nerve sheath tumor, and to a lesser extent, neuroblastoma, rhabdomyosarcoma, rhabdoid tumor, and high-grade glioma.
- Further preclinical studies are essential to optimize the use of CDK4/6 inhibitors in pediatric cancers.
- The interactive TAR heatmap provides a valuable resource for researchers and clinicians exploring CDK4/6 targeted therapies in pediatric oncology.
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