Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling by array of mesothelioma pre- and post-resistance biopsies in order to determine a resistance signature to pemetrexed/carboplatin treatment

ABSTRACT: Pemetrexed, a multi-folate inhibitor combined with a platinum compound is the first-line treatment of malignant mesothelioma, but median survival is still one year. Innate and acquired resistance to pemetrexed is common, but its biological basis is obscure. Here we report for the first time a genome-wide profile of acquired resistance in the tumour from an exceptional case with advanced pleural mesothelioma and almost six years survival after 39 cycles of second-line pemetrexed/carboplatin treatment.

ORGANISM(S): Homo sapiens

DISEASE(S): mesothelioma

SUBMITTER: Ryeng Einar

PROVIDER: E-MTAB-1109 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Molecular resistance fingerprint of pemetrexed and platinum in a long-term survivor of mesothelioma.

Røe Oluf Dimitri OD Szulkin Adam A Anderssen Endre E Flatberg Arnar A Sandeck Helmut H Amundsen Tore T Erlandsen Sten Even SE Dobra Katalin K Sundstrøm Stein Harald SH

PloS one 20120808 8

<h4>Background</h4>Pemetrexed, a multi-folate inhibitor combined with a platinum compound is the first-line treatment of malignant mesothelioma, but median survival is still one year. Intrinsic and acquired resistance to pemetrexed is common, but its biological basis is obscure. Here we report for the first time a genome-wide profile of acquired resistance in the tumour from an exceptional case with advanced pleural mesothelioma and almost six years survival after 39 cycles of second-line pemetr ...[more]

PMID: 22905093

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Project description:OBJECTIVE: Sorafenib is effective in hepatocellular carcinoma (HCC), but patients ultimately present disease progression. Molecular mechanisms underlying acquired resistance are still unknown. Herein, we characterize the role of tumor-initiating cells (T-ICs) and signaling pathways involved in sorafenib resistance. DESIGN: HCC xenograft mice treated with sorafenib (n=22) were explored for responsiveness (n=5) and acquired resistance (n=17). Mechanism of acquired resistance were assessed by: 1) Role of T-ICs by in vitro sphere formation and in vivo tumorigenesis assays using NOD/SCID mice, 2) Activation of alternative signaling pathways and 3) Efficacy of anti-FGF and anti-IGF drugs in experimental models. Gene expression (microarray, qRT-PCR) and protein analyses (immunohistochemistry, western blot) were conducted. A novel gene signature of sorafenib resistance was generated and tested in 2 independent cohorts. RESULTS: Sorafenib-acquired resistance tumors showed significant enrichment of T-ICs (164 cells needed to create a tumor) vs. sorafenib-sensitive tumors (13400 cells) and non-treated tumors (1292 cells), p<0.001. Tumors with sorafenib-acquired resistance were enriched with IGF and FGF signaling cascades (FDR<0.05). In vitro, cells derived from sorafenib-acquired resistant tumors and two sorafenib-resistant HCC cell lines were responsive to IGF or FGF inhibition. In vivo, FGF blockade delayed tumor growth and improved survival in sorafenib-resistant tumors. A sorafenib-resistance 175-gene signature was characterized by enrichment of progenitor-cell features, aggressive tumoral traits and predicted poor survival in 2 cohorts (n=442 HCC patients). CONCLUSION: Acquired resistance to sorafenib is driven by tumor initiating cells with enrichment of progenitor markers and activation of IGF and FGF signaling. Inhibition of these pathways would benefit a subset of patients after sorafenib progression. Transcriptomic profile of subcutaneous Huh7 cells-derived tumors treated with sorafenib that developed acquired resistance to the drug (n=4), remain responsive to sorafenib (n=3) or were treated with brivanib after development of resistance (n=3). Gene profiling of hepatospheres generated from tumors with acquired resistance to sorafenib (n=3) and non-treated tumors (n=3) was also analyzed.

Dataset Information

Transcription profiling by array of mesothelioma pre- and post-resistance biopsies in order to determine a resistance signature to pemetrexed/carboplatin treatment

Publications

Molecular resistance fingerprint of pemetrexed and platinum in a long-term survivor of mesothelioma.

Similar Datasets

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