Transcription profiling of human tumours at baseline and after 21 days of treatment with sorafenib and dacarbazine

ABSTRACT: Background New approaches are needed to improve prognostic accuracy for treatment response and to explore the complexities of drug effects on human tumours. We developed a strategy of global genomic investigation of sequential tumor biopsies at baseline and 21 days post-treatment, and applied this approach in a phase I study of sorafenib plus dacarbazine in patients with solid tumours. Methods 23 patients received 21-day cycles of oral sorafenib, 400 mg twice daily and dacarbazine, 1000 mg/m2 by 1-h intravenous infusion on day 1. Efficacy was assessed using response evaluation criteria in solid tumours. Differential gene expression was assessed through genomic microarray analysis of biopsy tissue from the same tumour at baseline and on day 21. Seven parameters characterizing vascularisation using dynamic enhanced-contrast ultrasonography (DCE-US) were assessed. Changes from baseline in the two parameters were characterized for patients with and without a clinical response to treatment at 3 months.Findings 23 patients were evaluable for efficacy and 17 for gene expression and DCE-US analyses. One patient had a partial response; 14 had stable disease. Genomic analyses identified a 247-gene signature that distinguished progressors from nonprogressors at 3 months. Expression of four genes was significantly associated with progression at 3 months. Functional parameters of DCE-US representing blood volume at baseline, day 8, and day 21 correlated with 3-month disease progression status.Interpretation This novel approach of sequential investigations in a phase I trial was feasible, detecting early changes in gene expression and tumour vascularity that may be predictive of clinical outcome.

ORGANISM(S): Homo sapiens

DISEASE(S): Epithelioid mesothelioma

SUBMITTER: Philippe DESSEN 

PROVIDER: E-TABM-760 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress