Targeting DNA repair pathways in cancer therapeutics
Alan D’Andrea
Dana-Farber Cancer Institute, Boston, USA
Cancer cells have genomic instability resulting from acquired defects in DNA repair. One DNA repair pathway—the Fanconi Anemia/BRCA homologous recombination pathway (Kennedy and D’Andrea, Genes&Development 19:2925, 2005) — is defective in many human cancers, including breast, ovarian, pancreatic, and lung neoplasms. Disruption of the FA/BRCA Pathway results in the characteristic chromosome instability and radiation/crosslinker hypersensitivity of these tumours. In general, loss of one DNA repair pathway often leads to hyperdependence on another pathway for tumour cell survival. This hyperdependence offers a unique opportunity for the development of anticancer therapeutics. For instance, FA/BRCA pathway deficient tumours are hyperdependent on Base Excision Repair (BER) and, accordingly, these tumours are hypersensitive to single agent treatment with PARP1 inhibitors which block BER. Our translational research program is focused on profiling the FA/BRCA pathway and the other five major DNA repair pathways in tumour cells (Kennedy and D’Andrea, JCO 24: 3799, 2006). Each DNA repair pathway has a characteristic protein biomarker and repairs a specific type of DNA lesion. By profiling these pathways in primary tumour samples with activation-specific antibodies to DNA repair proteins, we plan (1) to predict the sensitivity of tumours to conventional chemotherapy and radiation (so-called Personalized Medicine) (2) to subset tumours for their sensitivity to novel classes of DNA repair inhibitors, (i.e., PARP1, Chk1, and ATM inhibitors) and (3) to screen for new small molecule inhibitors of other DNA repair pathways. This combination of novel DNA repair inhibitors, conventional DNA damaging agents, and DNA repair biomarkers offers new opportunities for developing more effective anticancer therapy.
