Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Pemetrexed and gemcitabine as combination therapy for the treatment of Group3 medulloblastoma

ABSTRACT: We devised a high-throughput, cell-based assay to identify novel therapeutic compounds to treat Group3 medulloblastoma (G3 MB). Mouse G3 MBs, grown as neurospheres, were screened against a library of approximately 7,000 compounds including FDA-approved drugs. We identified two FDA-approved drugs, pemetrexed and gemcitabine that preferentially inhibited tumor proliferation in vitro compared to control neurospheres, and substantially inhibited tumor proliferation in vivo. When combined, the two drugs significantly increased survival P7 Trp53-/-, Cdkn2c-/- neurospheres and MYC mouse cells were compared treated and untreated with drugs pemetrexed+gemcitabine

ORGANISM(S): Mus musculus

SUBMITTER: David Finkelstein

PROVIDER: E-GEOD-46406 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Pemetrexed and gemcitabine as combination therapy for the treatment of Group3 medulloblastoma.

Morfouace Marie M Shelat Anang A Jacus Megan M Freeman Burgess B BB Turner David D Robinson Sarah S Zindy Frederique F Wang Yong-Dong YD Finkelstein David D Ayrault Olivier O Bihannic Laure L Puget Stephanie S Li Xiao-Nan XN Olson James M JM Robinson Giles W GW Guy R Kiplin RK Stewart Clinton F CF Gajjar Amar A Roussel Martine F MF

Cancer cell 20140327 4

We devised a high-throughput, cell-based assay to identify compounds to treat Group3 medulloblastoma (G3 MB). Mouse G3 MBs neurospheres were screened against a library of approximately 7,000 compounds including US Food and Drug Administration-approved drugs. We found that pemetrexed and gemcitabine preferentially inhibited G3 MB proliferation in vitro compared to control neurospheres and substantially inhibited G3 MB proliferation in vivo. When combined, these two drugs significantly increased s ...[more]

PMID: 24684846

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Project description:Identifying the Mechanism of Action (MoA) of drugs is critical for the development of new drugs, understanding their side effects, and drug repositioning. However, identifying drug MoA has been challenging and has been traditionally attempted only though large experimental setups with little success. While advances in computational power offers the opportunity to achieve this in-silico, methods to exploit existing computational resources are still in their infancy. To overcome this, we developed a novel method to identify Drug Mechanism of Action using Network Dysregulation (DeMAND). The method is based on the realization that drugs affect the protein activity of their targets, but not necessarily their mRNA expression levels. In contrast, the change in protein activity directly affects the mRNA expression levels of downstream genes. Based on this hypothesis, DeMAND identifies drug MoA by comparing gene expression profiles following drug perturbation with control samples, and computing the change in the individual interactions within a pre-determined integrated transcriptional and post-translational regulatory model (interactome). This dataset includes GEPs in 3 different B-cell lymphoma cell lines (OCI-LY3, OCI-LY7 and U2932) at 6, 12, and 24hrs. 92 FDA approved compounds were used at a concentration of IC20 at 24h. DMSO was used as control at each time-point. A total of 828 samples and 29 control samples were available for analysis. Total RNA was isolated with the RNAqueous-96 Automated Kit (Ambion) on the Janus automated liquid handling system (Perkin Elmer Inc.), quantified by NanoDrop 6000 spectrophotometer and quality checked by Agilent Bioanalyzer. 300ng of each of the samples with RIN value >7 were converted to biotinylated cRNA with the Illumina TotalPrep-96 RNA Amplification Kit (Ambion) using a standard T7-based amplification protocol and hybridized on the Human Genome U219 96-Array Plate (Affymetrix). Hybridization, washing, staining and scanning of the array plates were performed on the GeneTitan Instrument (Affymetrix) according to manufacturer’s protocols.

Dataset Information

Pemetrexed and gemcitabine as combination therapy for the treatment of Group3 medulloblastoma

Publications

Pemetrexed and gemcitabine as combination therapy for the treatment of Group3 medulloblastoma.

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