Co-clinical trials demonstrate predictive biomarkers for dovitinib, an FGFR inhibitor, in lung squamous cell carcinoma.

BACKGROUND: We conducted co-clinical trials in patient-derived xenograft (PDX) models to identify predictive biomarkers for the multikinase inhibitor dovitinib in lung squamous cell carcinoma (LSCC). METHODS: The PDX01-02 were established from LSCC patients enrolled in the phase II trial of dovitinib (NCT01861197) and PDX03-05 were established from LSCC patients receiving surgery. These five PDX tumors were subjected to in vivo test of dovitinib efficacy, whole exome sequencing and gene expression profiling. RESULTS: The PDX tumors recapitulate histopathological properties and maintain genomic characteristics of originating tumors. Concordant with clinical outcomes of the trial enrolled-LSCC patients, dovitinib produced substantial tumor regression in PDX-01 and PDX-05, whereas it resulted in tumor progression in PDX-02. PDX-03 and -04 also displayed poor antitumor efficacy to dovitinib. Mutational and genome-wide copy number profiles revealed no correlation between genomic alterations of FGFR1-3 and sensitivity to dovitinib. Of note, gene expression profiles revealed differentially expressed genes including FGF3 and FGF19 between PDX-01 and 05 and PDX-02-04. Pathway analysis identified two FGFR signaling-related gene sets, FGFR ligand binding/activation and SHC-mediated cascade pathway were substantially up-regulated in PDX-01 and 05, compared with PDX-02-04. The comparison of gene expression profiles between dovitinib-sensitive versus -resistant lung cancer cell lines in the Cancer Cell Line Encyclopedia database also found that transcriptional activation of 18 key signaling components in FGFR pathways can predict the sensitivity to dovitinib both in cell lines and PDX tumors. These results highlight FGFR pathway activation as a key molecular determinant for sensitivity to dovitinib. CONCLUSIONS: FGFR gene expression signatures are predictors for the response to dovitinib in LSCC.

Air pollution, weight loss and metabolic benefits of bariatric surgery: a potential model for study of metabolic effects of environmental exposures.

BACKGROUND: Emerging experimental evidence suggests that air pollution may contribute to development of obesity and diabetes, but studies of children are limited. OBJECTIVES: We hypothesized that pollution effects would be magnified after bariatric surgery for treatment of obesity, reducing benefits of surgery. METHODS: In 75 obese adolescents, excess weight loss (EWL), high-density lipoprotein (HDL) cholesterol, triglycerides, alkaline phosphatase (ALP) and hemoglobin A1c (HbA1c ) were measured prospectively at baseline and following laparoscopic adjustable gastric banding (LAGB). Residential distances to major roads and the average two-year follow-up exposure to particulate matter <2.5 µm (PM2.5 ), nitrogen dioxide (NO2 ) and ozone were estimated. Associations of exposure with change in outcome and with attained outcome two years post-surgery were examined. RESULTS: Major-roadway proximity was associated with reduced EWL and less improvement in lipid profile and ALP after surgery. NO2 was associated with less improvement in HbA1c and lower attained HDL levels and change in triglycerides over two years post-surgery. PM2.5 was associated with reduced EWL and reduced beneficial change or attained levels for all outcomes except HbA1c . CONCLUSIONS: Near-roadway, PM2.5 and NO2 exposures at levels common in developed countries were associated with reduced EWL and metabolic benefits of LAGB. This novel approach provides a model for investigating metabolic effects of other exposures.