Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Effect of AZA on gene expression of multiple breast, colon, and ovarian cell lines [expression]

ABSTRACT: Epigenetic therapy is emerging as a potential therapy for solid tumors. To investigate its mechanism of action, we performed integrative expression and methylation analysis of 63 cancer cell lines (breast, colorectal, and ovarian) after treatment with the DNA methyltransferase inhibitor 5-azacitidine (AZA). Gene Set Enrichment Analysis demonstrated significant enrichment for immunomodulatory pathways in all three cancers (14.4-31.3%) including interferon signaling, antigen processing and presentation, and cytokines/chemokines. Strong upregulation of cancer testis antigens was also observed. An AZA IMmune gene set (AIMs) derived from the union of these immunomodulatory pathway genes classified primary tumors from all three types, into M-bM-^@M-^\highM-bM-^@M-^] and M-bM-^@M-^\lowM-bM-^@M-^] AIM gene expression subsets in tumor expression data from both TCGA and GEO (GSE42284, GSE10893, and GSE26712 for the colon, breast, and ovarian samples, respectively). Samples from selected patient biopsies showed upregulation of AIM genes after treatment with epigenetic therapy. These results point to a broad immune stimulatory role for DNA demethylating drugs in multiple cancers. control vs. 5'-azacitidine-treated breast, colon, and ovarian cells at different time points (1, 3, 7, 10, 14, 21, or 28 days)

ORGANISM(S): Homo sapiens

SUBMITTER: Stephen Baylin

PROVIDER: E-GEOD-57341 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Immune regulation by low doses of the DNA methyltransferase inhibitor 5-azacitidine in common human epithelial cancers.

Li Huili H Chiappinelli Katherine B KB Guzzetta Angela A AA Easwaran Hariharan H Yen Ray-Whay Chiu RW Vatapalli Rajita R Topper Michael J MJ Luo Jianjun J Connolly Roisin M RM Azad Nilofer S NS Stearns Vered V Pardoll Drew M DM Davidson Nancy N Jones Peter A PA Slamon Dennis J DJ Baylin Stephen B SB Zahnow Cynthia A CA Ahuja Nita N

Oncotarget 20140201 3

Epigenetic therapy is emerging as a potential therapy for solid tumors. To investigate its mechanism of action, we performed integrative expression and methylation analysis of 63 cancer cell lines (breast, colorectal, and ovarian) after treatment with the DNA methyltransferase inhibitor 5-azacitidine (AZA). Gene Set Enrichment Analysis demonstrated significant enrichment for immunomodulatory pathways in all three cancers (14.4-31.3%) including interferon signaling, antigen processing and present ...[more]

PMID: 24583822

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Project description:In breast cancer models, combination epigenetic therapy with a DNA methyltransferase inhibitor and a histone deacetylase inhibitor led to reexpression of genes encoding important therapeutic targets, including the estrogen receptor (ER). We conducted a multicenter phase II study of 5-azacitidine and entinostat in women with advanced hormone-resistant or triple-negative breast cancer (TNBC). Purpose: In breast cancer models, combination epigenetic therapy with a DNA methyltransferase inhibitor and a histone deacetylase inhibitor led to re-expression of genes encoding important therapeutic targets including the estrogen receptor (ER). We conducted a multicenter phase II study of 5-azacitidine (AZA) and entinostat in women with advanced hormone-resistant or triple-negative breast cancer (TNBC). Patients and Methods: Patients received AZA 40 mg/m2 (days 1-5, 8-10) and entinostat 7 mg (days 3,10) of 28 day cycle. Continuation of epigenetic therapy was offered with addition of endocrine therapy at time of progression (optional continuation, OC phase). Primary endpoint was objective response rate (ORR) in each cohort. We hypothesized that ORR would be >20% against null of 5% using Simon two-stage design. At least 1 response was required in 1st of 13 patients per cohort to continue accrual to 27 per cohort. Type I error 4%, power 90%. Results: There was one partial response among 27 women with hormone-resistant disease (ORR=4%, 95% CI=0-19%), and none in 13 women with TNBC. One additional partial response was observed in the OC phase in the hormone-resistant cohort (n=12). Mandatory tumor samples were obtained pre- and post-treatment (58% paired) with either up- or down-regulation of ER observed in approximately 50% of post-treatment biopsies in the hormone-resistant, but not TNBC cohort. Conclusion: Combination epigenetic therapy was well tolerated but our primary endpoint was not met. OC phase results suggest that some women benefit from epigenetic therapy and/or reintroduction of endocrine therapy beyond progression but further study is needed.

Dataset Information

Effect of AZA on gene expression of multiple breast, colon, and ovarian cell lines [expression]

Publications

Immune regulation by low doses of the DNA methyltransferase inhibitor 5-azacitidine in common human epithelial cancers.

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