Targeting Fanconi anemia/BRCA2 pathway defects in cancer: the significance of preclinical pharmacogenomic models
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Published on: February 17, 2011
1The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, Maryland 21231, USA.
Abstract:
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.
Insights
Defects in the Fanconi anemia (FA) pathway are promising targets for cancer therapy due to cell hypersensitivity. Preclinical models are crucial for validating these targets and guiding clinical trials.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Fanconi anemia (FA) pathway defects are implicated in various human cancers.
- FA pathway-deficient cells exhibit hypersensitivity to DNA interstrand cross-linking agents.
Purpose of the Study:
- To validate and quantify FA pathway-deficient cell hypersensitivity in preclinical models.
- To evaluate combinational therapies and identify novel agents targeting FA pathway defects.
- To discuss limitations and artifacts in common FA models for therapeutic target validation.
Main Methods:
- Utilizing various preclinical pharmacogenomic models (in vitro and in vivo).
- Assessing hypersensitivity of engineered or naturally occurring FA pathway-deficient cells.
- Evaluating the impact of DNA interstrand cross-linking agents and other therapeutic modalities.
Main Results:
- FA pathway-deficient cells consistently demonstrate hypersensitivity to DNA interstrand cross-linking agents across diverse models.
- Robustness of this hypersensitivity is observable regardless of species, cell type, or engineering technique.
- Preclinical models show potential but require careful interpretation due to inherent artifacts.
Conclusions:
- FA pathway gene defects represent attractive targets for genotype-based, individualized anticancer therapy.
- The consistent hypersensitivity phenotype supports the clinical investigation of FA pathway targeting.
- Ongoing clinical trials are evaluating the therapeutic potential of targeting FA pathway defects in cancer.
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