Approaches for Identifying Novel Targets in Precision Medicine: Lessons from DNA Repair
Dean T Williams1,2, Christopher J Staples3
1School of Medical Sciences, Bangor University, Bangor, Gwynedd, LL57 2DG, UK.
Abstract:
Genome stability is maintained by a number of elegant mechanisms, which sense and repair damaged DNA. Germline defects that compromise genomic integrity result in cancer predisposition, exemplified by rare syndromes caused by mutations in certain DNA repair genes. These individuals often exhibit other symptoms including progeria and neurodegeneration. Paradoxically, some of these deleterious genetic alterations provide novel therapeutic opportunities to target cancer cells; an excellent example of such an approach being the recent development of poly (ADP-ribose) polymerase inhibitors as the first 'synthetic lethal' medicine for patients with BRCA-mutant cancers. The therapeutic exploitation of synthetic lethal interactions has enabled a novel approach to personalised medicine based on continued molecular profiling of patient and tumour material. This profiling may also aid clinicians in the identification of specific drug resistance mechanisms following relapse, and enable appropriate modification of the therapeutic regimen. This chapter focuses on therapeutic strategies designed to target aspects of the DNA damage response, and examines emerging themes demonstrating mechanistic overlap between DNA repair and neurodegeneration.
Insights
Defects in DNA repair mechanisms can lead to cancer and neurodegenerative diseases. Exploiting synthetic lethality, like with PARP inhibitors for BRCA-mutant cancers, offers personalized medicine and new therapeutic strategies.
Area of Science:
- Genetics and Molecular Biology
- Oncology
- Neuroscience
Background:
- Genome stability is crucial, maintained by DNA repair mechanisms.
- Defects in DNA repair genes cause cancer predisposition and syndromes with progeria and neurodegeneration.
- These genetic alterations paradoxically offer therapeutic targets in cancer.
Purpose of the Study:
- To explore therapeutic strategies targeting DNA damage response pathways.
- To examine the mechanistic overlap between DNA repair and neurodegeneration.
- To highlight the role of synthetic lethal interactions in personalized medicine.
Main Methods:
- Review of DNA repair mechanisms and their role in disease.
- Analysis of synthetic lethal interactions, exemplified by PARP inhibitors in BRCA-mutant cancers.
- Discussion of molecular profiling for personalized medicine and resistance mechanisms.
Main Results:
- Synthetic lethality provides a novel approach to cancer therapy.
- Molecular profiling aids in personalized treatment and managing drug resistance.
- Emerging themes show overlap between DNA repair and neurodegeneration.
Conclusions:
- Targeting DNA damage response pathways offers therapeutic opportunities.
- Personalized medicine, driven by molecular profiling, is advancing cancer treatment.
- Understanding DNA repair-neurodegeneration links may reveal new therapeutic avenues.
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