Cell Surface Expression and PET Imaging Establish DLL3 as a Clinically Actionable Target in Neuroblastoma

In adult neuroendocrine malignancies, including small cell lung cancer, Delta-like ligand 3 (DLL3) is a validated therapeutic target. DLL3 is expressed in neuroblastoma, a pediatric cancer of neuroendocrine origin, but subcellular localization is incompletely defined, limiting clinical translation of DLL3-targeted therapies for neuroblastoma. Methods: DLL3 expression and localization were evaluated in human neuroblastoma tumors and preclinical models using RNA sequencing, immunohistochemistry, and flow cytometry. To assess in vivo tumor accessibility, DLL3-targeted PET imaging with [⁸⁹Zr]Zr-deferoxamine-SC16.56 was performed in patient-derived xenograft (PDX) models and in 4 patients with neuroblastoma. Results: DLL3 was broadly expressed across neuroblastoma tumor samples and preclinical models. Although immunohistochemistry demonstrated variable protein expression, flow cytometry revealed near-universal DLL3 cell surface localization across clinical samples and PDX models, including tumors with low expression by immunohistochemistry. DLL3-targeted PET imaging demonstrated tumor-specific uptake in PDX models and in 4 patients with relapsed neuroblastoma, confirming in vivo accessibility of DLL3. Conclusion: DLL3 overexpression in neuroblastoma is associated with targetable cell surface localization, supporting DLL3 as a clinically actionable target for imaging and therapeutic strategies.