Targeted Disruption of FANCC and FANCG in Human Cancer Provides a Preclinical Model for Specific Therapeutic Options

Gallmeier, Eike; Calhoun, Eric S.; Rago, Carlo; Brody, Jonathan R.; Cunningham, Steven C.; Hucl, Tomáš; Gorospe, Myriam; Kohli, Manu; Lengauer, Christoph; Kern, Scott E.

doi:10.1053/j.gastro.2006.03.016

Cited by 52 publications

(62 citation statements)

References 29 publications

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“…Fancd2-deficient zebrafish embryos develop a smaller body due to extensive apoptosis (66). In human cancer cells, we found the engineered disruption of the proximal FA genes FANCC and FANCG, but not of the distal FANCD2 and BRCA2, to yield viable clones (46). 1 Consistently, mutations of the proximal FANCC and FANCG, but not of the distal FANCD2, are reported.…”

Section: Pharmacogenomic Fa Modelssupporting

confidence: 64%

“…FA pathway-deficient cells are hypersensitive to certain therapeutics, particularly interstrand cross-linking agents (13) and some poly(ADP-ribose) polymerase inhibitors (39 -44). Their sensitivity to irradiation remains controversial (45,46). An important challenge will be the identification and development of novel agents to which FA pathway-deficient cells are hypersensitive.…”

Section: Clinical Translational Advancesmentioning

confidence: 99%

“…The FA genes are involved in the regulation of cell cycle controls, DNA repair, and genome maintenance, features that are expected to differ between malignant and nonmalignant cells. FA models that use cancer cells may therefore be preferable for pharmacogenomic studies because it is uncertain whether the FA phenotype of nonmalignant cells can be fully extrapolated to malignant cells (46). Table 1 lists many of the presently available human cancer FA lines.…”

Section: Pharmacogenomic Fa Modelsmentioning

confidence: 99%

“…The extent of hypersensitivity is best described by the IC 50 ratios between FA pathway-proficient and FA pathway-deficient cells, here termed the pharmacogenomic window. The width of this pharmacogenomic window depends on the specific interstrand cross-linking agent used and might reflect the proportional contribution of interstrand cross-links to the overall toxicity of the drug (46). IC 50 ratios of z10-fold, generally regarded as promising for further clinical evaluation, can be achieved in preclinical FA cancer models on treatment with several interstrand cross-linking agents (e.g., melphalan, mitomycin C, and carboplatin; ref.…”

Section: The Robust Hypersensitivity Of Fa Pathwaydeficient Cells To mentioning

confidence: 99%

“…IC 50 ratios of z10-fold, generally regarded as promising for further clinical evaluation, can be achieved in preclinical FA cancer models on treatment with several interstrand cross-linking agents (e.g., melphalan, mitomycin C, and carboplatin; ref. 46). …”

Section: The Robust Hypersensitivity Of Fa Pathwaydeficient Cells To mentioning

confidence: 99%

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Targeting Fanconi Anemia/BRCA2 Pathway Defects in Cancer: The Significance of Preclinical Pharmacogenomic Models

Gallmeier

Kern

2007

Clinical Cancer Research

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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.

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Section: Pharmacogenomic Fa Modelssupporting

confidence: 64%

Section: Clinical Translational Advancesmentioning

confidence: 99%

Section: Pharmacogenomic Fa Modelsmentioning

confidence: 99%

Section: The Robust Hypersensitivity Of Fa Pathwaydeficient Cells To mentioning

confidence: 99%

Section: The Robust Hypersensitivity Of Fa Pathwaydeficient Cells To mentioning

confidence: 99%

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Targeting Fanconi Anemia/BRCA2 Pathway Defects in Cancer: The Significance of Preclinical Pharmacogenomic Models

Gallmeier

Kern

2007

Clinical Cancer Research

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Genome Annotation by Shotgun Inactivation of a Native Gene in Hemizygous Cells: Application toBRCA2with Implication of Hypomorphic Variants

et al. 2015

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The greatest interpretive challenge of modern medicine may be to functionally annotate the vast variation of human genomes. Demonstrating a proposed approach, we created a library of BRCA2 exon 27 shotgun-mutant plasmids including solitary and multiplex mutations to generate human knockin clones using homologous recombination. This 55-mutation, 13-clone syngeneic variance library (SyVaL) comprised severely affected clones having early-stop nonsense mutations, functionally hypomorphic clones having multiple missense mutations emphasizing the potential to identify and assess hypomorphic mutations in novel proteomic and epidemiologic studies, and neutral clones having multiple missense mutations. Efficient coverage of nonessential amino acids was provided by mutation multiplexing. Severe mutations were distinguished from hypomorphic or neutral changes by chemosensitivity assays (hypersensitivity to mitomycin C and acetaldehyde), by analysis of RAD51 focus formation, and by mitotic multipolarity. A multiplex unbiased approach of generating all-human SyVaLs in medically important genes, with random mutations in native genes, would provide databases of variants that could be functionally annotated without concerns arising from exogenous cDNA constructs or interspecies interactions, as a basis for subsequent proteomic domain mapping or clinical calibration if desired. Such gene-irrelevant approaches could be scaled up for multiple genes of clinical interest, providing distributable cellular libraries linked to public-shared functional databases.

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The complexity of pancreatic ductal cancers and multidimensional strategies for therapeutic targeting

Kern

Shi

Hruban

2010

The Journal of Pathology

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The directions of differentiation and the molecular features of ductal pancreatic cancer have by now been explored in reasonable detail. Already, diagnoses and therapeutic strategies benefit from observations distinguishing the major variant types of pancreatic cancer and the differing stages of disease at presentation. Additionally, individual patients differ within each variant type. In certain high-risk groups, this permits focused screening efforts. The tumorigenic influences that characterize individual patients are increasingly considered appropriate in defining clinical treatment plans. As a result, multiple variables affect success when individualizing screening or therapy. These competing variables often limit the potential for success: some variables dominate and should receive greater consideration than others. Simplistic expectations, often falsely optimistic, for individualized care may fail to ‘pan out’ in the real world. The development of individualized care will be efficient only when the full complexity of the disease is embraced.

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Targeted Disruption of FANCC and FANCG in Human Cancer Provides a Preclinical Model for Specific Therapeutic Options

Cited by 52 publications

References 29 publications

Targeting Fanconi Anemia/BRCA2 Pathway Defects in Cancer: The Significance of Preclinical Pharmacogenomic Models

Targeting Fanconi Anemia/BRCA2 Pathway Defects in Cancer: The Significance of Preclinical Pharmacogenomic Models

Genome Annotation by Shotgun Inactivation of a Native Gene in Hemizygous Cells: Application toBRCA2with Implication of Hypomorphic Variants

The complexity of pancreatic ductal cancers and multidimensional strategies for therapeutic targeting

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