Targeting Fanconi anemia/BRCA2 pathway defects in cancer: the significance of preclinical pharmacogenomic models.
Defects in the Fanconi anemia (FA) pathway occur in subsets of diverse human cancers. The hypersensitivity of FA pathway-deficient cells to DNA interstrand cross-linking and possibly other agents renders these genes attractive targets for a genotype-based, individualized anticancer therapy. A prerequisite before clinical trials is the validation and quantification of this hypersensitivity in suitable preclinical pharmacogenomic models. In addition, the effects of combinational therapy need to be evaluated and novel agents sought. We discuss here the pitfalls and limitations in the interpretation of common FA models when applied to the validation of FA gene defects as therapeutic targets. In general, all preclinical models are prone to certain artifacts and, thus, promising results in a single or few models rarely translate into clinical success. Nevertheless, the extraordinary robustness of FA pathway-deficient cells to interstrand cross-linking agents, which are observable in virtually any model independent of species, cell type, or technique used to engineer the gene defect, in various in vitro and in vivo settings, renders these gene defects particularly attractive for targeted therapy. Clinical trials are now under way.
Gallmeier
Eike
E
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, Maryland 21231, USA.
Kern
Scott E
SE
D000818:Animals; D024682:BRCA2 Protein / Q000378:metabolism*; D045744:Cell Line, Tumor; D003432:Cross-Linking Reagents / Q000494:pharmacology; D051856:Fanconi Anemia Complementation Group Proteins / Q000378:metabolism / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism*; D010597:Pharmacogenetics / Q000379:methods*
D024682:BRCA2 Protein; D003432:Cross-Linking Reagents; D051856:Fanconi Anemia Complementation Group Proteins