TY - CHAP

T1 - Approaches for Identifying Novel Targets in Precision Medicine

T2 - Lessons from DNA Repair

AU - Williams, Dean T

AU - Staples, Christopher

PY - 2017/8/25

Y1 - 2017/8/25

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1007/978-3-319-60733-7_1

DO - 10.1007/978-3-319-60733-7_1

M3 - Chapter

C2 - 28840549

SN - 978-3-319-60731-3

VL - 1007

T3 - Advances in Experimental Medicine and Biology

SP - 1

EP - 16

BT - Personalised Medicine

A2 - El-Khamisy, S.

PB - Springer

ER -