Immunomodulatory action of the DNA methyltransferase inhibitor SGI-110 in epithelial ovarian cancer cells and xenografts

Srivastava, Pragya; Paluch, Benjamin E.; Matsuzaki, Junko; James, Smitha R.; Collamat-Lai, Golda; Taverna, Pietro; Karpf, Adam R.; Griffiths, Elizabeth A.

doi:10.1080/15592294.2015.1017198

Cited by 69 publications

(47 citation statements)

References 40 publications

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“…In AML xenografts, SGI110 upregulates NY-ESO-1 and MAGE-A and induces cytotoxicity by CD8+ T cells specific for NY-ESO-1 (47). Similar results were observed in epithelial ovarian cancer (EOC) xenografts (48). These promising results led to a Phase I clinical trial in EOC in which Odunsi et al added Dac to NY-ESO-1 vaccine combined with doxorubicin chemotherapy in patients with relapsed EOC.…”

Section: Pre-clinical Studies Show That Epigenetic Therapy Drugs Boossupporting

confidence: 76%

Combining Epigenetic and Immunotherapy to Combat Cancer

et al. 2016

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The most exciting recent advance for achieving durable management of advanced human cancers is immune therapy, especially the concept of immune checkpoint blockade. However, with the exception of melanoma, most patients do not respond to immune therapy alone. A growing body of work has shown that epigenetic drugs, specifically DNA methyltransferase inhibitors, can upregulate immune signaling in epithelial cancer cells through demethylation of endogenous retroviruses and cancer testis antigens. These demethylating agents may induce T-cell attraction and enhance immune checkpoint inhibitor efficacy in mouse models. Current clinical trials are testing this combination therapy as a potent new cancer management strategy.

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Section: Pre-clinical Studies Show That Epigenetic Therapy Drugs Boossupporting

confidence: 76%

Combining Epigenetic and Immunotherapy to Combat Cancer

et al. 2016

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“…However, our data suggest that CT45 based vaccination approaches might be most beneficial when occurring in the context of co-treatments that induce CT45 expression in vivo. Epigenetic modulators such as decitabine, SGI-110, or similar agents, may be well suited for utilization in this context 39,40 . Finally, we point out that the emerging oncogenic functions of CT45 suggest that therapeutics that directly target this protein family could also have utility in cancers that commonly express these proteins, including ER-negative breast cancer and HGSOC.…”

Section: Discussionmentioning

confidence: 99%

DNA hypomethylation-mediated activation ofCancer/Testis Antigen 45(CT45) genes is associated with disease progression and reduced survival in epithelial ovarian cancer

et al. 2015

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Epithelial ovarian cancer (EOC) is a highly lethal malignancy due to a lack of early detection approaches coupled with poor outcomes for patients with clinically advanced disease. Cancer-testis (CT) or cancer-germline genes encode antigens known to generate spontaneous anti-tumor immunity in cancer patients. CT45 genes are a recently discovered 6-member family of X-linked CT genes with oncogenic function. Here, we determined CT45 expression in EOC and fully defined its epigenetic regulation by DNA methylation. CT45 was silent and hypermethylated in normal control tissues, but a large subset of EOC samples showed increased CT45 expression in conjunction with promoter DNA hypomethylation. In contrast, copy number status did not correlate with CT45 expression in the TCGA database for EOC. CT45 promoter methylation inversely correlated with both CT45 mRNA and protein expression, the latter determined using IHC staining of an EOC TMA. CT45 expression was increased and CT45 promoter methylation was decreased in late-stage and high-grade EOC, and both measures were associated with poor survival. CT45 hypomethylation was directly associated with LINE-1 hypomethylation, and CT45 was frequently co-expressed with other CT antigen genes in EOC. Decitabine treatment induced CT45 mRNA and protein expression in EOC cells, and promoter transgene analyses indicated that DNA methylation directly represses CT45 promoter activity. These data verify CT45 expression and promoter hypomethylation as possible prognostic biomarkers, and suggest CT45 as an immunological or therapeutic target in EOC. Treatment with decitabine or other epigenetic modulators could provide a means for more effective immunological targeting of CT45.

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“…In malignant mesothelioma, the expression of NY-ESO-1 is increased through histone deacetylase inhibitor [32]. Studies conducted using ovarian cancer cell lines have reported that the expression level of NY-ESO-1 was increased using DNA methylation inhibitors [33], indicating that epigenetic mechanisms such as acetylation and methylation may be involved in NY-ESO-1 expression. We found almost no gene mutation or ampli cation for the 14 antigens and antibodies that we selected in our study.…”

Section: Discussionmentioning

confidence: 99%

Inducing multiple antibodies to treat squamous cell esophageal carcinoma

Hoshino

Nabeya

Takiguchi

et al. 2020

Preprint

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Background The positive response and the clinical usefulness of 14 serum antibodies in patients with esophageal squamous cell carcinoma (ESCC) were examined in this study. The Cancer Genome Atlas (TCGA) was used to investigate the frequency of gene expressions, mutations, and amplification of these 14 antigens and also the possible effects of antibody induction. Methods Blood serum derived from 85 patients with ESCC was collected and analyzed for the 14 antibodies using ELISA. The prognosis between positive and negative antibodies were then compared. The antibody panel included galectin1, HCA25a, HCC-22-5, and HSP70. Results Patient serum was positive for all antibodies, except VEGF, with the positive rates ranging from 1.18% to 10.59%. Positive rates for galectin1, HCA25a, HCC-22-5, and HSP70 were >10%. TCGA data revealed that all antigen-related genes had little or no mutation or amplification, and hence an increase in gene expression affected antibody induction. The positive results from the panel accounted for the positive rate comparable to the combination of CEA and SCC. No significant association was observed between the presence of antibodies and disease prognosis. Conclusions The detection rates of galectin1, HCA25a, HCC-22-5, and HSP70 were 10% higher in patients with ESCC. Gene overexpression may be involved in such antibody production. These four antibodies were applied as a panel in comparison with conventional tumor markers. Moreover, it was confirmed that the combination of this panel and the conventional tumor markers significantly improved the positive rate.

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Immunomodulatory action of the DNA methyltransferase inhibitor SGI-110 in epithelial ovarian cancer cells and xenografts

Cited by 69 publications

References 40 publications

Combining Epigenetic and Immunotherapy to Combat Cancer

Combining Epigenetic and Immunotherapy to Combat Cancer

DNA hypomethylation-mediated activation ofCancer/Testis Antigen 45(CT45) genes is associated with disease progression and reduced survival in epithelial ovarian cancer

Inducing multiple antibodies to treat squamous cell esophageal carcinoma

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