Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Gene expression data from human metastatic melanoma tumors that may predict response to RAF265

ABSTRACT: To determine how mutation of BRAF affected the response to RAF265, we utilized a tumor orthotopic implant model of early passage melanoma tumors in nude mice from a series of 17 patients with advanced metastatic Tumor growth was compared between RAF265 treatment (40 mg/kg, QD) and diluent control groups. The melanoma associated gene mutation profile and global gene expression profile were determined on these human melanoma samples by SNaPshot and Affymetrix Human Gene ST 1.0 Array, respectively. Tumors were evaluated for growth response to RAF265 in an orthotopic implant model using nude mice. Comparisons were made between gene expression profiles of responders and non-responders, BRAF mutant and BRAF wild type tumors. Analysis of the microarray data revealed responders exhibited enriched expression of genes involved in cell cycle, apoptosis, cell-cell adhesion and initiation of epithelial/mesenchymal transition. It is concluded that RAF265 significantly inhibits the growth of a sub-population of V600E mutant and wild type BRAF human melanoma tumors in vivo and the gene expression profile of this subset of tumors that may predict response to RAF265. RNA from 17 human metastatic melanoma tumors was extracted and hybridized on Affymetrix microarrays.

ORGANISM(S): Homo sapiens

SUBMITTER: Pengcheng Lu

PROVIDER: E-GEOD-30812 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

RAF265 inhibits the growth of advanced human melanoma tumors.

Su Yingjun Y Vilgelm Anna E AE Kelley Mark C MC Hawkins Oriana E OE Liu Yan Y Boyd Kelli L KL Kantrow Sara S Splittgerber Ryan C RC Short Sarah P SP Short Sarah P SP Sobolik Tammy T Zaja-Milatovic Snjezana S Dahlman Kimberly Brown KB Amiri Katayoun I KI Jiang Aixiang A Lu Pengcheng P Shyr Yu Y Stuart Darrin D DD Levy Shawn S Sosman Jeffrey A JA Richmond Ann A

Clinical cancer research : an official journal of the American Association for Cancer Research 20120220 8

<h4>Purpose</h4>The purpose of this preclinical study was to determine the effectiveness of RAF265, a multikinase inhibitor, for treatment of human metastatic melanoma and to characterize traits associated with drug response.<h4>Experimental design</h4>Advanced metastatic melanoma tumors from 34 patients were orthotopically implanted to nude mice. Tumors that grew in mice (17 of 34) were evaluated for response to RAF265 (40 mg/kg, every day) over 30 days. The relation between patient characteris ...[more]

PMID: 22351689

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Project description:Melanoma is the deadliest form of skin cancer with rising incidence and mortality rates. Oncogenic mutation in BRAF gene is the single most frequent genetic alteration in human melanoma; however, this event per se is not sufficient to produce melanoma in vivo. We have investigated whether epigenetic changes, specifically aberrant DNA methylation and dysregulation of gene expression, alone or in combination with this genetic event, are involved in the genesis of human melanoma. We have constructed the whole M-bM-^@M-^XM-bM-^@M-^Xof primary human melanomas in relation to their BRAF mutational status. Our methylation profiling identified a large number of hyper- or hypomethylated genes in melanoma tumors, many of which being novel and having the potential to serve as biomarkers. Gene ontology analysis revealed that gene categories involved in neuronal cell morphology and development, and skin and neurological disorders were highly enriched. Frequently methylated targets included developmental regulatory transcription factors and homeobox genes, which are mostly subjected to bivalent histone marking and Polycomb occupancy in embryonic stem cells. Notably, several genes involved in the MEK-ERK and the PI3K pathways, two of the most frequently perturbed pathways in human melanoma, showed extensive methylation changes. Gene expression profiling identified a long list of dysregulated genes, many of which being involved in melanocytes development and differentiation, and showing concomitant aberrant DNA methylation. Sub-typing of the melanoma tumors based on BRAF mutational status revealed that tumors with a mutated BRAF had distinctive and more pronounced changes in both DNA methylation and gene expression profiles than tumors carrying the wildtype BRAF. The differentially compromised methylome and transcriptome of melanomas (dependent on BRAF mutation) deserves special attention because many epigenetic alterations, including DNA methylation-mediated regulation of gene expression, are potentially reversible. The dichotomous integrity of epigenome in human melanoma holds great promise for the field of personalized medicine. Methylome: Eleven primary human melanoma speciemens versus five normal human melanocyte samples. Transcriptome: Ten primary human melanoma speciemens versus four normal human melanocyte samples

Project description:Melanoma is the deadliest form of skin cancer with rising incidence and mortality rates. Oncogenic mutation in BRAF gene is the single most frequent genetic alteration in human melanoma; however, this event per se is not sufficient to produce melanoma in vivo. We have investigated whether epigenetic changes, specifically aberrant DNA methylation and dysregulation of gene expression, alone or in combination with this genetic event, are involved in the genesis of human melanoma. We have constructed the whole ‘‘of primary human melanomas in relation to their BRAF mutational status. Our methylation profiling identified a large number of hyper- or hypomethylated genes in melanoma tumors, many of which being novel and having the potential to serve as biomarkers. Gene ontology analysis revealed that gene categories involved in neuronal cell morphology and development, and skin and neurological disorders were highly enriched. Frequently methylated targets included developmental regulatory transcription factors and homeobox genes, which are mostly subjected to bivalent histone marking and Polycomb occupancy in embryonic stem cells. Notably, several genes involved in the MEK-ERK and the PI3K pathways, two of the most frequently perturbed pathways in human melanoma, showed extensive methylation changes. Gene expression profiling identified a long list of dysregulated genes, many of which being involved in melanocytes development and differentiation, and showing concomitant aberrant DNA methylation. Sub-typing of the melanoma tumors based on BRAF mutational status revealed that tumors with a mutated BRAF had distinctive and more pronounced changes in both DNA methylation and gene expression profiles than tumors carrying the wildtype BRAF. The differentially compromised methylome and transcriptome of melanomas (dependent on BRAF mutation) deserves special attention because many epigenetic alterations, including DNA methylation-mediated regulation of gene expression, are potentially reversible. The dichotomous integrity of epigenome in human melanoma holds great promise for the field of personalized medicine.

Dataset Information

Gene expression data from human metastatic melanoma tumors that may predict response to RAF265

Publications

RAF265 inhibits the growth of advanced human melanoma tumors.

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