TY - JOUR
T1 - Pathway for the Development of ATR Inhibitors in Pediatric Malignancies
T2 - An ACCELERATE Multistakeholder Analysis
AU - Gatz, Susanne A
AU - Glade-Bender, Julia
AU - Pearson, Andrew D J
AU - Ortiz, Michael V
AU - Bernardi, Ronald
AU - Chesler, Lou
AU - Clifford, Steve
AU - Cohen-Gogo, Sarah
AU - De La Cuesta, Esther
AU - de Rojas, Teresa
AU - Durinck, Kaat
AU - Federico, Sara
AU - Fox, Elizabeth
AU - George, Sally
AU - Gounaris, Ioannis
AU - Henssen, Anton George
AU - Irwin, Meredith
AU - Kool, Marcel
AU - Lau, Alan
AU - Nysom, Karsten
AU - Pappo, Alberto
AU - Pennock, Gregory K
AU - Pfister, Stefan M
AU - Scobie, Nicole
AU - Slotkin, Emily K
AU - Smith, Malcolm
AU - Speleman, Frank
AU - Stewart, Elizabeth A
AU - Weigel, Brenda J
AU - Vassal, Gilles
PY - 2026/1
Y1 - 2026/1
N2 - 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.
AB - 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.
KW - Humans
KW - Ataxia Telangiectasia Mutated Proteins/antagonists & inhibitors
KW - Child
KW - Neoplasms/drug therapy
KW - Neuroblastoma/drug therapy
KW - Sarcoma, Ewing/drug therapy
KW - Protein Kinase Inhibitors/therapeutic use
U2 - 10.1200/PO-25-00642
DO - 10.1200/PO-25-00642
M3 - Review article
C2 - 41538758
SN - 2473-4284
VL - 10
JO - JCO Precision Oncology
JF - JCO Precision Oncology
M1 - e2500642
ER -