Abstract 5403: Targeting death-receptors in therapy resistant progressive neuroblastoma: A preliminary insight

Neuroblastoma is the most common cancer in infants and accounts for 9.1% of childhood cancer-related deaths. Despite the current standard of care (SOC), drug-resistant neuroblastoma significantly compromises patient survival. Hence it is critical to identify new and less toxic therapeutic approaches for better patient outcomes. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which mediates its effect through the activation of the death receptor (DR) 4 and 5 are found on many cell types and are the main pathway for apoptosis. These can death receptors can kill most tumor cell types expressing TRAIL-receptor 1. Mining RNA-Seq data across multiple cohorts of neuroblastoma patients indicated that high levels of DR4 and DR5 significantly associated with poor clinical outcomes (OS, EFS, RFS). Further, examining the surface expression of DR4 and DR5 by immunohistochemistry using anti-human rabbit monoclonal antibodies on custom-archived TMAs for 100 NB patients revealed profound correlation with poor OS and RFS. Immunoblot analysis for DR4 and DR5 level in a panel of stage 4 patient-derived cell-lines during diagnosis and from progressive disease after therapy displayed high-levels of death receptor expression in progressive disease. Preliminary co-culture investigations with genetically engineered mesenchymal stem cells (MSCs) expressing tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) mimicking targeted delivery showed heightened differentiation and death (limited dilution tumorosphere assay) of therapy resistant cells. Further these studies exhibited inhibition of tumor cell migration and invasion. The results demonstrate the benefit of targeted TRAIL delivery in in the treatment of therapy resistant neuroblastoma and further imply that the genetically engineered MSCs could serve as a clinically valuable tool for improved therapeutic strategy in this setting. Citation Format: Dinesh Babu Somasundaram, Andrew Maher, Sheeja Aravindan, Terence S. Herman, Natarajan Aravindan. Targeting death-receptors in therapy resistant progressive neuroblastoma: A preliminary insight [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5403.