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Author Spotlight: Developing Novel Anticancer Therapeutics Targeting the DNA Damage Response
Published on: June 14, 2024
Targeting the DNA Damage Response for the Treatment of High Risk Neuroblastoma
Harriet E D Southgate1, Lindi Chen1, Nicola J Curtin2
1Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
Abstract:
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.
Insights
High-risk neuroblastoma (HR-NB) has poor survival rates. This review explores exploiting DNA damage response (DDR) defects in HR-NB with novel molecular agents to improve patient outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- High-risk neuroblastoma (HR-NB) has a survival rate below 50% despite intensive multimodal therapy.
- Relapse with treatment-resistant disease is common, necessitating novel therapeutic strategies.
- Defects in DNA damage response (DDR) pathways are prevalent in HR-NB.
Purpose of the Study:
- To review the genetic features of HR-NB that lead to DDR defects.
- To explore emerging molecular targeting agents that exploit these DDR vulnerabilities.
- To identify potential new therapeutic strategies for HR-NB.
Main Methods:
- Literature review of genetic alterations in HR-NB.
- Analysis of studies on DNA damage response (DDR) pathways in neuroblastoma.
- Review of preclinical and clinical data on molecular targeting agents for HR-NB.
Main Results:
- HR-NB frequently exhibits DDR defects, including gene deletions, mutations, replication stress, and checkpoint dysfunction.
- Exploiting DDR defects has shown promise in other cancers.
- Emerging molecular agents are being developed to target these specific vulnerabilities in HR-NB.
Conclusions:
- Targeting DDR defects represents a promising therapeutic avenue for HR-NB.
- Further research into molecular targeting agents is crucial for improving survival rates in HR-NB.
- Understanding the genetic landscape of HR-NB is key to developing effective treatments.
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