Targeting the DNA Damage Response for the Treatment of High Risk Neuroblastoma

• Main Authors: Harriet E. D. Southgate, Lindi Chen, Nicola J. Curtin, Deborah A. Tweddle
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2020-04-01
• Series: Frontiers in Oncology
• Subjects: neuroblastoma; DNA damage response; targeted therapy; PARP; ATR
• Online Access: https://www.frontiersin.org/article/10.3389/fonc.2020.00371/full

Despite intensive multimodal therapy, the survival rate for high risk neuroblastoma (HR-NB) remains <50%. Most cases initially respond to treatment but almost half will subsequently relapse with aggressive treatment resistant disease. Novel treatments exploiting the molecular pathology of NB and/or overcoming resistance to current genotoxic therapies are needed before survival rates can significantly improve. DNA damage response (DDR) defects are frequently observed in HR-NB including allelic deletion and loss of function mutations in key DDR genes, oncogene induced replication stress and cell cycle checkpoint dysfunction. Exploiting defects in the DDR has been a successful treatment strategy in some adult cancers. Here we review the genetic features of HR-NB which lead to DDR defects and the emerging molecular targeting agents to exploit them.