title: Molecular Pathways: Targeting DNA Repair Pathway Defects Enriched in Metastasis.
abstract: The maintenance of a pristine genome, free from errors, is necessary to prevent cellular transformation and degeneration. When errors in DNA are detected, DNA damage repair (DDR) genes and their regulators are activated to effect repair. When these DDR pathways are themselves mutated or aberrantly downregulated, cancer and neurodegenerative disorders can ensue. Multiple lines of evidence now indicate, however, that defects in key regulators of DNA repair pathways are highly enriched in human metastasis specimens and hence may be a key step in the acquisition of metastasis and the ability of localized disease to disseminate. Some of the key regulators of checkpoints in the DNA damage response are the TP53 protein and the PARP enzyme family. Targeting of these pathways, especially through PARP inhibition, is now being exploited therapeutically to effect significant clinical responses in subsets of individuals, particularly in patients with ovarian cancer or prostate cancer, including cancers with a marked metastatic burden. Targeting DNA repair-deficient tumors with drugs that take advantage of the fundamental differences between normal repair-proficient cells and repair-deficient tumors offers new avenues for treating advanced disease in the future. Clin Cancer Res; 22(13); 3132-7. ©2016 AACR.
authors.affiliation: Department of Surgery, Division of Urology, Royal Melbourne Hospital and University of Melbourne and The Epworth Prostate Centre, Epworth Hospital, Victoria, Australia.
authors.forename: Niall M
authors.initials: NM
authors.lastname: Corcoran
authors.affiliation: Department of Surgery, Division of Urology, Royal Melbourne Hospital and University of Melbourne and The Epworth Prostate Centre, Epworth Hospital, Victoria, Australia.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Clarkson
authors.affiliation: Department of Surgery, Division of Urology, Royal Melbourne Hospital and University of Melbourne and The Epworth Prostate Centre, Epworth Hospital, Victoria, Australia.
authors.forename: Ryan
authors.initials: R
authors.lastname: Stuchbery
authors.affiliation: Department of Surgery, Division of Urology, Royal Melbourne Hospital and University of Melbourne and The Epworth Prostate Centre, Epworth Hospital, Victoria, Australia. chovens@unimelb.edu.au.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Hovens
mesh_terms: D059447:Cell Cycle Checkpoints / Q000187:drug effects; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000187:drug effects* / Q000502:physiology; D005260:Female; D006801:Humans; D008297:Male; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000627:therapeutic use*; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D011065:Poly(ADP-ribose) Polymerases