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- W2275055972 abstract "8575 Background: The multi-tyrosine kinase inhibitor sorafenib affects the Raf/Mek/Erk and VEGF pathway. The therapy impact on in vivo metabolic activity and transcriptional profiling was investigated. Methods: Single-arm investigator-initiated pilot study enrolled 13 first-line stage IV MM patients (LDH > 1.1 ULN) with metastases accessible for repeated biopsies. Patients were treated with sorafenib (400 mg bid, day 1-56) and DTIC (1,000 mg/m2, day 14, 42). Primary endpoints were changes in glucose uptake (PERCIST 1.0), S100 and LDH serum levels. Secondary endpoints were determination of differentially expressed genes and alternative splicing events during treatment. PET/CT, serum S100, LDH and biopsies were taken on screening, day 10, 16, and 60. Transcriptional profiling was performed using Human Exon 1.0 WT microarrays (Affymetrix). Differentially expressed genes and alternative splicing events were determined by R-Bioconductor using exonmap, limma, stats and samr packages. Enrichment analysis was performed using Genego Metacore. Results: At day 60, 5 responders and 8 non-responders (clinical and metabolic) were observed. Glucose uptake was inversely associated with response (p = 0.003) with a significant decrease of S100 in responders (p = 0.01), but not of LDH (p = 0.8, 2-tailed Mann-Whitney test). Transcriptional analysis of day 10 biopsies detected PEG10, HIGD2A, TOM1L1 for responders, and GMGF, CD163, CD53 for non-responders as top differentially expressed genes. Glucose metabolism network provided the best tool for hierarchical sample classification into responders and non-responders, confirming the in vivo data. JAK, TGFbeta and PIK3 signaling pathways, xenobiotic metabolism, DNA repair and vascularization processes were upregulated in non-regressive, but stress-induced metabolism and transcriptional reorganization networks in regressive lesions. Conclusions: Reduced glucose uptake by MM metastases under sorafenib predicts tumor regression. Metabolic tumor response is associated with distinctive molecular signatures on the transcriptional level and may contribute to rational personalized treatment approaches in MM patients. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer Bayer Bayer" @default.
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- W2275055972 date "2010-05-20" @default.
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- W2275055972 title "In vivo metabolic activity and transcriptional profiling in melanoma (MM) patients during sorafenib and dacarbazine (DTIC) treatment." @default.
- W2275055972 doi "https://doi.org/10.1200/jco.2010.28.15_suppl.8575" @default.
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