Combining Epigenetic and Immunotherapy to Combat Cancer

Chiappinelli, Katherine B.; Zahnow, Cynthia A.; Ahuja, Nita; Baylin, Stephen B.

doi:10.1158/0008-5472.can-15-2125

Cited by 264 publications

(215 citation statements)

References 74 publications

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“…This finding is consistent with previous reports showing that CTAs are epigenetically activated in multiple cancers (45) and that the expression of CTAs can be activated by a demethylating agent (46,47). Upregulation of CTAs as immunogenic targets by a demethylating agent could be therapeutically attractive, in particular in combination with immunotherapy in NSCLC (48,49). However, we note that three epi-markers activated by a demethylating agent (MYEOV, ARL14, and LINC00857) were also associated with poor prognosis, which can have implications when considering demethylating agents for therapeutic use in NSCLC, as oncogenic/carcinogenic genes can be activated by such treatment.…”

Section: Discussionsupporting

confidence: 92%

Integrative CAGE and DNA Methylation Profiling Identify Epigenetically Regulated Genes in NSCLC

Horie

Kaczkowski²,

Ohshima

et al. 2017

Molecular Cancer Research

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Section: Discussionsupporting

confidence: 92%

Integrative CAGE and DNA Methylation Profiling Identify Epigenetically Regulated Genes in NSCLC

Horie

Kaczkowski²,

Ohshima

et al. 2017

Molecular Cancer Research

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“…2I). These data highlight the concept that epigenetic therapy, including KDM5i, may be able to improve the efficacy of immunotherapy (38). …”

Section: Resultsmentioning

confidence: 63%

A KDM5 Inhibitor Increases Global H3K4 Trimethylation Occupancy and Enhances the Biological Efficacy of 5-Aza-2′-Deoxycytidine

Leadem

Kagiampakis

Wilson³

et al. 2018

Cancer Research

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The H3K4 demethylase KDM5B is amplified and overexpressed in luminal breast cancer, suggesting it might constitute a potential cancer therapy target. Here we characterize, in breast cancer cells, the molecular effects of a recently developed small-molecule inhibitor of the KDM5 family of proteins (KDM5i), either alone or in combination with the DNA demethylating agent 5-aza-2′-deoxycytidine (DAC). KDM5i treatment alone increased expression of a small number of genes, whereas combined treatment with DAC enhanced the effects of the latter for increasing expression of hundreds of DAC-responsive genes. ChIP-seq studies revealed that KDM5i resulted in the broadening of existing H3K4me3 peaks. Furthermore, cells treated with the drug combination exhibited increased promoter and gene body H3K4me3 occupancy at DAC-responsive genes compared to DAC alone. Importantly, treatment with either DAC or DAC+KDM5i induced a dramatic increase in H3K27ac at enhancers with an associated significant increase in target gene expression, suggesting a previously unappreciated effect of DAC on transcriptional regulation. KDM5i synergized with DAC to reduce the viability of luminal breast cancer cells in in-vitro assays. Our study provides the first look into the molecular effects of a novel KDM5i compound and suggests that combinatorial inhibition along with DAC represents a new area to explore in translational epigenetics.

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“…A number of small molecule inhibitors have been developed to target epigenetic mechanisms (so-called epidrugs) and there is increasing interest in using these compounds in solo or combination treatments for cancer [106][107][108][109][110]. Thus far, the DNMT inhibitors, 5-AzaC and 5-AzaDC, and the HDAC inhibitors, vorinostat and romidepsin, have been approved by the US FDA for use future science group Epigenetic control of the tumor microenvironment Review in humans [37].…”

Section: Opportunities To Epigenetically Remodel Stromal Cellsmentioning

confidence: 99%

Epigenetic Control of the Tumor Microenvironment

2016

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Stromal cells of the tumor microenvironment have been shown to play important roles in both supporting and limiting cancer growth. The altered phenotype of tumorassociated stromal cells (fibroblasts, immune cells, endothelial cells etc.) is proposed to be mainly due to epigenetic dysregulation of gene expression; however, only limited studies have probed the roles of epigenetic mechanisms in the regulation of stromal cell function. We review recent studies demonstrating how specific epigenetic mechanisms (DNA methylation and histone post-translational modification-based gene expression regulation, and miRNA-mediated translational regulation) drive aspects of stromal cell phenotype, and discuss the implications of these findings for treatment of malignancies. We also summarize the effects of epigenetic mechanismtargeted drugs on stromal cells and discuss the consideration of the microenvironment response in attempts to use these drugs for cancer treatment.

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Combining Epigenetic and Immunotherapy to Combat Cancer

Cited by 264 publications

References 74 publications

Integrative CAGE and DNA Methylation Profiling Identify Epigenetically Regulated Genes in NSCLC

Integrative CAGE and DNA Methylation Profiling Identify Epigenetically Regulated Genes in NSCLC

A KDM5 Inhibitor Increases Global H3K4 Trimethylation Occupancy and Enhances the Biological Efficacy of 5-Aza-2′-Deoxycytidine

Epigenetic Control of the Tumor Microenvironment

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