Search tips
Search criteria

Results 1-8 (8)

Clipboard (0)

Select a Filter Below

Year of Publication
Document Types
1.  Frequent and Focal FGFR1 Amplification Associates With Therapeutically Tractable FGFR1 Dependency in Squamous-cell Lung Cancer 
Science translational medicine  2010;2(62):62ra93.
Lung cancer remains one of the leading causes for cancer-related death in developed countries. In lung adenocarcinomas, EGFR mutations and EML4-ALK fusions are associated with response to EGFR and ALK inhibition. By contrast, therapeutically exploitable genetic alterations have been lacking in squamous-cell lung cancer. We conducted a systematic search for alterations that are therapeutically amenable and performed high-resolution gene-copy number analyses in a set of 232 lung cancer specimens. We identified frequent and focal FGFR1 amplification in squamous-cell lung cancer (n=155), but not in other lung cancer subtypes, and confirmed its presence in an independent cohort of squamous-cell lung cancer samples employing FISH (22% of cases). Using cell-based screening with the FGFR inhibitor (PD173074) in a large (n=83) panel of lung cancer cell lines, we demonstrated that this compound inhibited growth (p=0.0002) and induced apoptosis (p=0.008) specifically in those lung cancer cells carrying amplified FGFR1. We validated the dependency on FGFR1 of FGFR1-amplified cell lines by knockdown of FGFR1 and by ectopic expression of a resistance allele of FGFR1 (FGFR1V561M), which rescued FGFR1-amplified cells from PD173074-mediated cytotoxicity. Finally we showed that inhibition of FGFR1 with a small molecule led to significant tumor shrinkage in vivo. Focal FGFR1 amplification is common in squamous-cell lung cancer and associated with tumor growth and survival, suggesting that FGFR inhibitors may be a viable therapeutic option in this cohort of patients.
PMCID: PMC3990281  PMID: 21160078
2.  Correcting for the influence of sampling conditions on biomarkers of exposure to phenols and phthalates: a 2-step standardization method based on regression residuals 
Environmental Health  2012;11:29.
Environmental epidemiology and biomonitoring studies typically rely on biological samples to assay the concentration of non-persistent exposure biomarkers. Between-participant variations in sampling conditions of these biological samples constitute a potential source of exposure misclassification. Few studies attempted to correct biomarker levels for this error. We aimed to assess the influence of sampling conditions on concentrations of urinary biomarkers of select phenols and phthalates, two widely-produced families of chemicals, and to standardize biomarker concentrations on sampling conditions.
Urine samples were collected between 2002 and 2006 among 287 pregnant women from Eden and Pélagie cohorts, from which phthalates and phenols metabolites levels were assayed. We applied a 2-step standardization method based on regression residuals. First, the influence of sampling conditions (including sampling hour, duration of storage before freezing) and of creatinine levels on biomarker concentrations were characterized using adjusted linear regression models. In the second step, the model estimates were used to remove the variability in biomarker concentrations due to sampling conditions and to standardize concentrations as if all samples had been collected under the same conditions (e.g., same hour of urine collection).
Sampling hour was associated with concentrations of several exposure biomarkers. After standardization for sampling conditions, median concentrations differed by ‒ 38 % for 2,5-dichlorophenol to +80 % for a metabolite of diisodecyl phthalate. However, at the individual level, standardized biomarker levels were strongly correlated (correlation coefficients above 0.80) with unstandardized measures.
Sampling conditions, such as sampling hour, should be systematically collected in biomarker-based studies, in particular when the biomarker half-life is short. The 2-step standardization method based on regression residuals that we proposed in order to limit the impact of heterogeneity in sampling conditions could be further tested in studies describing levels of biomarkers or their influence on health.
PMCID: PMC3533777  PMID: 22537080
Biomarker; Endocrine Disruptor; Phenols; Phthalate esters; Pregnancy; Sampling conditions
3.  Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer 
Cancer discovery  2011;1(1):78-89.
While genomically targeted therapies have improved outcomes for patients with lung adenocarcinoma, little is known about the genomic alterations which drive squamous cell lung cancer. Sanger sequencing of the tyrosine kinome identified mutations in the DDR2 kinase gene in 3.8% of squamous cell lung cancers and cell lines. Squamous lung cancer cell lines harboring DDR2 mutations were selectively killed by knock-down of DDR2 by RNAi or by treatment with the multi-targeted kinase inhibitor dasatinib. Tumors established from a DDR2 mutant cell line were sensitive to dasatinib in xenograft models. Expression of mutated DDR2 led to cellular transformation which was blocked by dasatinib. A squamous cell lung cancer patient with a response to dasatinib and erlotinib treatment harbored a DDR2 kinase domain mutation. These data suggest that gain-of-function mutations in DDR2 are important oncogenic events and are amenable to therapy with dasatinib. As dasatinib is already approved for use, these findings could be rapidly translated into clinical trials.
PMCID: PMC3274752  PMID: 22328973
Squamous cell lung cancer; DDR2; dasatinib; tyrosine kinase inhibitors; lung cancer genomics
4.  Exposure to Phthalates and Phenols during Pregnancy and Offspring Size at Birth 
Environmental Health Perspectives  2011;120(3):464-470.
Background: Data concerning the effects of prenatal exposures to phthalates and phenols on fetal growth are limited in humans. Previous findings suggest possible effects of some phenols on male birth weight.
Objective: Our aim was to assess the relationships between prenatal exposures to phthalates and phenols and fetal growth among male newborns.
Methods: We conducted a case–control study on male malformations of the genitalia nested in two French mother–child cohorts with recruitment between 2002 and 2006. We measured, in maternal urinary samples collected between 6 and 30 gestational weeks, the concentrations (micrograms per liter) of 9 phenol (n = 191 pregnant women) and 11 phthalate metabolites (n = 287). Weight, length, and head circumference at birth were collected from maternity records. Statistical analyses were corrected for the oversampling of malformation cases.
Results: Adjusted birth weight decreased by 77 g [95% confidence interval (CI): –129, –25] and by 49 g (95% CI: –86, –13) in association with a 1-unit increase in ln-transformed 2,4-dichlorophenol (DCP) and 2,5-DCP urinary concentrations, respectively. Benzophenone-3 (BP3) ln-transformed concentrations were positively associated with weight (26 g; 95% CI: –2, 54) and head circumference at birth (0.1 cm; 95% CI: 0.0, 0.2). Head circumference increased by 0.3 cm (95% CI: 0.0, 0.7) in association with a 1-unit increase in ln-transformed BPA concentration. For phthalate metabolites there was no evidence of monotonic associations with birth weight.
Conclusions: Consistent with findings of a previous study, we observed evidence of an inverse association of 2,5-DCP and a positive association of BP3 with male birth weight.
PMCID: PMC3295340  PMID: 21900077
birth outcomes; fetal growth; phenols; phthalates; pregnancy exposure; urinary biomarkers
5.  Systems medicine and integrated care to combat chronic noncommunicable diseases 
Genome Medicine  2011;3(7):43.
We propose an innovative, integrated, cost-effective health system to combat major non-communicable diseases (NCDs), including cardiovascular, chronic respiratory, metabolic, rheumatologic and neurologic disorders and cancers, which together are the predominant health problem of the 21st century. This proposed holistic strategy involves comprehensive patient-centered integrated care and multi-scale, multi-modal and multi-level systems approaches to tackle NCDs as a common group of diseases. Rather than studying each disease individually, it will take into account their intertwined gene-environment, socio-economic interactions and co-morbidities that lead to individual-specific complex phenotypes. It will implement a road map for predictive, preventive, personalized and participatory (P4) medicine based on a robust and extensive knowledge management infrastructure that contains individual patient information. It will be supported by strategic partnerships involving all stakeholders, including general practitioners associated with patient-centered care. This systems medicine strategy, which will take a holistic approach to disease, is designed to allow the results to be used globally, taking into account the needs and specificities of local economies and health systems.
PMCID: PMC3221551  PMID: 21745417
6.  Clinically Relevant Characterization of Lung Adenocarcinoma Subtypes Based on Cellular Pathways: An International Validation Study 
PLoS ONE  2010;5(7):e11712.
Lung adenocarcinoma (AD) represents a predominant type of lung cancer demonstrating significant morphologic and molecular heterogeneity. We sought to understand this heterogeneity by utilizing gene expression analyses of 432 AD samples and examining associations between 27 known cancer-related pathways and the AD subtype, clinical characteristics and patient survival. Unsupervised clustering of AD and gene expression enrichment analysis reveals that cell proliferation is the most important pathway separating tumors into subgroups. Further, AD with increased cell proliferation demonstrate significantly poorer outcome and an increased solid AD subtype component. Additionally, we find that tumors with any solid component have decreased survival as compared to tumors without a solid component. These results lead to the potential to use a relatively simple pathological examination of a tumor in order to determine its aggressiveness and the patient's prognosis. Additional results suggest the ability to use a similar approach to determine a patient's sensitivity to targeted treatment. We then demonstrated the consistency of these findings using two independent AD cohorts from Asia (N = 87) and Europe (N = 89) using the identical analytic procedures.
PMCID: PMC2908611  PMID: 20661423
7.  Cooperation of amphiregulin and insulin-like growth factor-1 inhibits Bax- and Bad-mediated apoptosis via a protein kinase C-dependent pathway in non-small cell lung cancer cells 
The Journal of Biological Chemistry  2005;280(20):19757-19767.
Amphiregulin (AR) and insulin-like growth factor-1 (IGF1) are growth factors known to promote non-small cell lung cancer (NSCLC) survival. We have previously published that 1) AR and IGF1, secreted by H358 NSCLC cells, cooperate to protect those cells and H322 NSCLC cells from serum-starved apoptosis; 2) H358 cells resist to Bax-induced apoptosis through an inhibition of Bax conformational change. We show here that the anti-apoptotic activity of AR/IGF1 combination is specifically abolished by the PKC inhibitors calphostin C and staurosporine, but not by the MAPK and PI3K inhibitors PD98059 and wortmannin, suggesting the involvement of a PKC-dependent, MAPK- and PI3K-independent survival pathway. The PKCδ inhibitor rottlerin restores apoptosis induced by serum deprivation. In addition, phosphorylation of PKCδ and PKCζ/λ, but not of PKCα/βII, increases in serum-starved H358 cells and in H322 cells treated with AR/IGF1 combination and is blocked by calphostin C. Combination of AR and IGF1 increases p90Rsk and Bad phosphorylation as well as it inhibits the conformational change of Bax by a PKC-dependent mechanism. Finally, PKCδ, PKCζ or p90Rsk siRNAs block the anti-apoptotic activity of AR/IGF1 combination but have no effect on partial apoptosis inhibition observed with each factor used alone. Constitutively active PKC expression inhibits serum deprivation-induced apoptosis, whereas a catalytically inactive form of p90Rsk restores it. Thus, AR and IGF1 cooperate to prevent apoptosis by activating a specific PKC-p90Rsk-dependent pathway, which leads to Bad and Bax inactivation. This signalling pathway is different to that used by single factor.
PMCID: PMC2685917  PMID: 15767261
1-Phosphatidylinositol 3-Kinase; antagonists & inhibitors; Androstadienes; pharmacology; Apoptosis; drug effects; physiology; Carcinoma, Non-Small-Cell Lung; pathology; physiopathology; Carrier Proteins; antagonists & inhibitors; physiology; Cell Line, Tumor; Culture Media, Serum-Free; Enzyme Inhibitors; pharmacology; Flavonoids; pharmacology; Glycoproteins; physiology; Humans; Insulin-Like Growth Factor I; physiology; Intercellular Signaling Peptides and Proteins; physiology; Isoenzymes; antagonists & inhibitors; physiology; Lung Neoplasms; pathology; physiopathology; MAP Kinase Signaling System; drug effects; Models, Biological; Naphthalenes; pharmacology; Protein Kinase C; antagonists & inhibitors; physiology; Proto-Oncogene Proteins c-bcl-2; antagonists & inhibitors; physiology; Signal Transduction; drug effects; Staurosporine; pharmacology; bcl-2-Associated X Protein; bcl-Associated Death Protein

Results 1-8 (8)