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Pathway for the Development of ATR Inhibitors in Pediatric Malignancies: An ACCELERATE Multistakeholder Analysis
Susanne A Gatz1,2, Julia Glade-Bender3, Andrew D J Pearson4
1Department of Cancer and Genomic Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham, United Kingdom.
Purpose:
High levels of DNA replication stress and defects in the DNA damage response (DDR) pathways are vulnerabilities of many poor prognosis childhood malignancies. Ataxia telangiectasia and Rad3-related protein (ATR) is a key regulator of these pathways and constitutes an attractive target, especially in combination. However, the malignancies where ATR inhibitors have maximum benefit and synergistic combinations differ between adults and children.
Design:
ACCELERATE convened a multistakeholder meeting and conducted review and analysis to propose the optimal pathway for the development of ATR inhibitors in pediatric malignancies.
Results:
Considering the lack of identified biomarkers, the initial evaluation of ATR inhibitors should focus on Ewing sarcoma, rhabdomyosarcoma, and neuroblastoma in view of their high levels of DNA replication stress and defects in DDR pathways. Early phase trials of ATR inhibitors should be iterative, based on a clear hypothesis with responders and nonresponders undergoing detailed molecular analysis and a revised new hypothesis generated. Trial designs should restrict monotherapy evaluation to a brief exposure in a small number of patients and progress rapidly to combinations. Highlighted combination partners are poly(ADP-ribose) polymerase inhibitors and antibody drug conjugates with topoisomerase I inhibitor payloads. Combinations with ALK inhibitors (in ALK/MYCN-aberrant neuroblastoma) and aurora A kinase (in MYCN-amplified) are supported by robust mechanisms of action and preclinical data. Early interactions with regulators are crucial, and early phase clinical trials should be conducted in regulatory-approved, academic-sponsored, industry-supported, platform trials.
Conclusion:
ATR inhibitors are a prototype for the development of medicinal products in a limited pediatric population. For the substantial potential of ATR inhibitors in children with malignancy to be realized, strategic planning between academia, industry, regulators, and patient advocates is vital.
Insights
Pediatric cancers with DNA replication stress may benefit from Ataxia telangiectasia and Rad3-related protein (ATR) inhibitors. Strategic planning is vital for developing these targeted therapies in children.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Childhood malignancies often exhibit high DNA replication stress and DNA damage response (DDR) pathway defects, presenting therapeutic vulnerabilities.
- Ataxia telangiectasia and Rad3-related protein (ATR) is a crucial regulator of DDR pathways, making it an attractive therapeutic target, particularly in combination therapies.
- Optimal development strategies for ATR inhibitors in pediatric cancers differ from adult indications.
Purpose of the Study:
- To propose an optimal development pathway for Ataxia telangiectasia and Rad3-related protein (ATR) inhibitors in pediatric malignancies.
- To identify specific childhood cancers where ATR inhibitors may offer maximum benefit.
- To outline effective clinical trial designs and combination strategies for ATR inhibitors in pediatric oncology.
Main Methods:
- Convened a multistakeholder meeting involving experts in pediatric oncology and drug development.
- Conducted a comprehensive review and analysis of existing data on ATR inhibitors and pediatric malignancies.
- Synthesized findings to propose a strategic development pathway, including trial design and combination approaches.
Main Results:
- Initial evaluation of ATR inhibitors should focus on Ewing sarcoma, rhabdomyosarcoma, and neuroblastoma due to high replication stress and DDR defects.
- Early phase trials should be iterative, hypothesis-driven, and incorporate detailed molecular analysis of responders and non-responders.
- Recommended combinations include PARP inhibitors, antibody-drug conjugates with topoisomerase I payloads, ALK inhibitors (for specific neuroblastoma subtypes), and aurora A kinase inhibitors.
- Emphasized the need for early regulatory interaction and conducting trials within regulatory-approved, academic-sponsored, industry-supported platform trials.
Conclusions:
- Ataxia telangiectasia and Rad3-related protein (ATR) inhibitors represent a prototype for targeted therapy development in pediatric populations.
- Realizing the potential of ATR inhibitors in children requires strategic collaboration between academia, industry, regulators, and patient advocates.
- A well-defined, collaborative strategy is essential for the successful clinical development of ATR inhibitors in pediatric cancer.
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