Phase Ib/II study of safety and efficacy of low‐dose decitabine‐primed chemoimmunotherapy in patients with drug‐resistant relapsed/refractory alimentary tract cancer

Chen, Meixia; Nie, Jing; Liu, Yang; Li, Xiang; Zhang, Yan; Brock, Malcolm V.; Feng, Kang; Wu, Zhiqiang; Li, Xiaolei; Shi, Lu; Li, Suxia; Guo, Mingzhou; Mei, Qian; Han, Weidong

doi:10.1002/ijc.31531

Cited by 20 publications

(16 citation statements)

References 48 publications

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“…Decitabine is a drug used to treat myelodysplastic syndromes that inhibited EMT by regulating the miR‐200/ZEB signaling pathway in non–small‐cell lung cancer PC9 cells . In addition, a phase Ib/II clinical trial revealed that low‐dose decitabine enhanced the efficacy of immunotherapy in patients with drug‐resistant relapsed/refractory alimentary tract cancer, making it an attractive therapy for cancers …”

Section: Small Molecules Against Emtmentioning

confidence: 97%

“…58 In addition, a phase Ib/II clinical trial revealed that low-dose decitabine enhanced the efficacy of immunotherapy in patients with drug-resistant relapsed/refractory alimentary tract cancer, making it an attractive therapy for cancers. 104 Silibinin, a bioactive component from Silybum marianum (L.) Gaertn., exhibited anticancer properties in multiple types of cancer, such as bladder and lung cancer ( Table 1). Recent studies revealed that silibinin reversed EMT by inhibiting the expression of ZEB1, vimentin, and MMP-2 as well as the transactivation of βcatenin in bladder cancer metastasis.…”

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confidence: 99%

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Small molecule inhibitors of epithelial‐mesenchymal transition for the treatment of cancer and fibrosis

Feng

Chen

Vaziri

et al. 2019

Medicinal Research Reviews

109

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Tissue fibrosis and cancer both lead to high morbidity and mortality worldwide; thus, effective therapeutic strategies are urgently needed. Because drug resistance has been widely reported in fibrotic tissue and cancer, developing a strategy to discover novel targets for targeted drug intervention is necessary for the effective treatment of fibrosis and cancer. Although many factors lead to fibrosis and cancer, pathophysiological analysis has demonstrated that tissue fibrosis and cancer share a common process of epithelial‐mesenchymal transition (EMT). EMT is associated with many mediators, including transcription factors (Snail, zinc‐finger E‐box‐binding protein and signal transducer and activator of transcription 3), signaling pathways (transforming growth factor‐β1, RAC‐α serine/threonine‐protein kinase, Wnt, nuclear factor‐kappa B, peroxisome proliferator‐activated receptor, Notch, and RAS), RNA‐binding proteins (ESRP1 and ESRP2) and microRNAs. Therefore, drugs targeting EMT may be a promising therapy against both fibrosis and tumors. A large number of compounds that are synthesized or derived from natural products and their derivatives suppress the EMT by targeting these mediators in fibrosis and cancer. By targeting EMT, these compounds exhibited anticancer effects in multiple cancer types, and some of them also showed antifibrotic effects. Therefore, drugs targeting EMT not only have both antifibrotic and anticancer effects but also exert effective therapeutic effects on multiorgan fibrosis and cancer, which provides effective therapy against fibrosis and cancer. Taken together, the results highlighted in this review provide new concepts for discovering new antifibrotic and antitumor drugs.

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Section: Small Molecules Against Emtmentioning

confidence: 97%

mentioning

confidence: 99%

Small molecule inhibitors of epithelial‐mesenchymal transition for the treatment of cancer and fibrosis

Feng

Chen

Vaziri

et al. 2019

Medicinal Research Reviews

109

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“…DNA demethylating drugs, 5-azacytidine (azacytidine) and 5-aza-2′-deoxycytidine (decitabine, DAC), are now clinically used for patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) [ 3 – 5 ]. Also in solid tumors, clinical trials using these demethylating drugs are being actively conducted [ 6 , 7 ], and efficacy has already been shown for various types of solid tumors, such as recurrent metastatic non-small cell lung cancer [ 8 ], platinum-resistant ovarian cancers [ 9 ], advanced hepatocellular carcinomas [ 10 ], and drug-resistant relapsed/refractory alimentary tract cancers [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Low-dose DNA demethylating therapy induces reprogramming of diverse cancer-related pathways at the single-cell level

Takeshima¹,

Yoda

Wakabayashi³

et al. 2020

Clin Epigenet

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Background Epigenetic reprogramming using DNA demethylating drugs is a promising approach for cancer therapy, but its efficacy is highly dependent on the dosing regimen. Low-dose treatment for a prolonged period shows a remarkable therapeutic efficacy, despite its small demethylating effect. Here, we aimed to explore the mechanisms of how such low-dose treatment shows this remarkable efficacy by focusing on epigenetic reprograming at the single-cell level. Methods Expression profiles in HCT116 cells treated with decitabine (DAC) were analyzed by single-cell RNA-sequencing (scRNA-seq). Functional consequences and DNA demethylation at the single-cell level were analyzed using cloned HCT116 cells after DAC treatment. Results scRNA-seq revealed that DAC-treated cells had highly diverse expression profiles at the single-cell level, and tumor-suppressor genes, endogenous retroviruses, and interferon-stimulated genes were upregulated in random fractions of cells. DNA methylation analysis of cloned HCT116 cells revealed that, while only partial reduction of DNA methylation levels was observed in bulk cells, complete demethylation of specific cancer-related genes, such as cell cycle regulation, WNT pathway, p53 pathway, and TGF-β pathway, was observed, depending upon clones. Functionally, a clone with complete demethylation of CDKN2A (p16) had a larger fraction of cells with tetraploid than parental cells, indicating induction of cellular senescence due to normalization of cell cycle regulation. Conclusions Epigenetic reprogramming of specific cancer-related pathways at the single-cell level is likely to underlie the remarkable efficacy of low-dose DNA demethylating therapy.

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“…Chemical agents such as 5-azacytidine and 5-aza-2′-deoxycytidine, which inhibit methylation by binding to and inhibiting DNMT enzyme, are now being tested in phase II-III studies [35][36][37][38]. Furthermore, use of oligonucleotides that bind to promoter regions at specific gene level and perform gene inhibition is seen as approaches that may contribute to cancer treatments [39][40][41].…”

Section: Resultsmentioning

confidence: 99%

Logic of Epigenetics and Investigation of Potential Gene Regions

Budak¹

2020

Chromatin and Epigenetics

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In living organisms, all molecular structures are formed, and all events are carried out by specific DNA sequences referred to as ‛genes'. However, these genes need to be governed and controlled to function properly. In this way, they can participate in biological processes at the optimal time. Genes are actively controlled by other genes and specific proteins called ‛transcription factors'. In addition, there is another mechanism that determines gene expression, which can be transmitted from generation to generation and from cell to cell. This mechanism is referred to as the ‛epigenetic code'. The DNA sequence does not undergo any changes during the formation of this code, but the relevant part of DNA fragment becomes no longer meaningful. While histone modifications control expression of DNA in chromosome structure, methylation modifications at the gene level are quite effective in controlling expressions the cytosine-end methylation seen in mammalian genome often occurs in the nucleotide pairs which are also called the CpG dinucleotides. The most common epigenetic modifications are the changes in histone proteins and DNA methylation, and the most widely studied and the most wellestablished epigenetic mechanism is the latter.

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Phase Ib/II study of safety and efficacy of low‐dose decitabine‐primed chemoimmunotherapy in patients with drug‐resistant relapsed/refractory alimentary tract cancer

Cited by 20 publications

References 48 publications

Small molecule inhibitors of epithelial‐mesenchymal transition for the treatment of cancer and fibrosis

Small molecule inhibitors of epithelial‐mesenchymal transition for the treatment of cancer and fibrosis

Low-dose DNA demethylating therapy induces reprogramming of diverse cancer-related pathways at the single-cell level

Logic of Epigenetics and Investigation of Potential Gene Regions

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