4SC-202 as a Potential Treatment for the Pediatric Brain Tumor Medulloblastoma

Messerli, Shanta M.; Hoffman, Mariah M.; Gnimpieba, Etienne Z.; Kohlhof, Hella; Bhardwaj, Ratan D.

doi:10.3390/brainsci7110147

Cited by 19 publications

(11 citation statements)

References 22 publications

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“…The inhibition of PTK7 has been suggested as a novel therapeutic target for various cancers such as colorectal cancer and atypical teratoid rhabdoid tumors 31 , 32 , and some anticancer agents under development involve PTK7-targeted antibody-drug conjugates 33 or PTK7 aptamers 34 . However, caution should be used with this strategy when considering the evidence showing PTK7 can biphasically regulate tumorigenesis, as the inhibition of PTK7 activity or removal of PTK7-positive cells may induce tumor progression.…”

Section: Discussionmentioning

confidence: 99%

Biphasic regulation of tumorigenesis by PTK7 expression level in esophageal squamous cell carcinoma

Shin

Gim

Won

et al. 2018

Sci Rep

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Protein tyrosine kinase 7 (PTK7), also known as colon carcinoma kinase 4 (CCK-4), is a member of the catalytically defective receptor protein tyrosine kinase family and is upregulated in various cancers, where it is known to act as either an oncoprotein or a tumor suppressor. To understand the contrasting roles of PTK7 in tumorigenesis, we analyzed the tumorigenic characteristics of esophageal squamous cell carcinoma (ESCC) cells with low levels of endogenous PTK7 expression (TE-5 and TE-14 cells) and high levels of expression (TE-6 and TE-10 cells) after transfections with a PTK7 expression vector. PTK7 overexpression increased the proliferation of TE-5 and TE-14 cells but decreased the proliferation of TE-6 and TE-10 cells. In the ESCC cells, proliferation, migration, and invasion were initially increased and then decreased according to PTK7 expression levels, which were mirrored by initial increases and then decreases in the tyrosine phosphorylation of cellular proteins and phosphorylation of Src, Akt, and ERK. In ESCC patients included in The Cancer Genome Atlas database, those with higher PTK7 mRNA levels had a longer overall survival and lower relative risk than those with lower PTK7 mRNA levels. These results demonstrate that PTK7 biphasically regulates tumorigenesis in ESCC.

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Section: Discussionmentioning

confidence: 99%

Biphasic regulation of tumorigenesis by PTK7 expression level in esophageal squamous cell carcinoma

Shin

Gim

Won

et al. 2018

Sci Rep

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“…In medulloblastoma, domatinostat treatment inhibits cell viability and downregulates hedgehog signaling significantly. Upregulated proteins such as HDAC2 and HDAC3 are key targets for domatinostat in medulloblastoma (Messerli et al, 2017).…”

Section: Increased Expression Of Apm Genes and Mhc Class I Surface Momentioning

confidence: 99%

The HDAC Inhibitor Domatinostat Promotes Cell-Cycle Arrest, Induces Apoptosis, and Increases Immunogenicity of Merkel Cell Carcinoma Cells

Song

Bretz²,

Gravemeyer

et al. 2021

Journal of Investigative Dermatology

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…A number of studies support that 4SC-202 exerts cytotoxic effects by inducing apoptosis in established hepatocarcinoma cell lines and patient-derived cells, colorectal cancer cells, Myelodysplastic Syndrome cells, and human medulloblastoma cells [15][16][17]57], and combined apoptosis and necrosis pathways in urothelial carcinoma cells [13]. The results from the systems biology analysis indicate that genes involved in the negative regulation of apoptosis may be overexpressed.…”

Section: Discussionmentioning

confidence: 97%

“…In multiple cancer cell lines and preclinical models, 4SC-202 has exerted anti-tumor activities [13][14][15]. We have previously published that 4SC-202 significantly reduces the viability of medulloblastoma in culture [16]. Pre-clinical studies performed in hepatocellular carcinoma, medulloblastoma, urothelial carcinoma, and colon cancer indicate that 4SC-202 inhibits cell proliferation, induces apoptosis, inhibits mitosis, and is efficacious in vivo, causing a reduction of tumor growth in a number of different mouse xenograft studies including Hedgehog driven basal cell carcinoma (BCC) and a colorectal cancer murine model [12,13,15,17,18].…”

Section: Introductionmentioning

confidence: 99%

“…While preclinical studies have demonstrated the efficacy of 4SC-202 in some models, the mechanism by which 4SC-202 exerts anti-cancer effects stills needs further characterization. Prior studies indicate 4SC-202 may target cancer stem cells [20] and other studies have demonstrated that 4SC-202 blocks hedgehog (HH)/Gli signaling in a human medulloblastoma model [12,16]. Hedgehog signaling has been shown to play a role in the maintenance of stem cells [21].…”

Section: Introductionmentioning

confidence: 99%

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Analysis of Dual Class I Histone Deacetylase and Lysine Demethylase Inhibitor Domatinostat (4SC-202) on Growth and Cellular and Genomic Landscape of Atypical Teratoid/Rhabdoid

Hoffman

Zylla

Bhattacharya

et al. 2020

Cancers

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Central nervous system atypical teratoid/rhabdoid tumors (ATRTs) are rare and aggressive tumors with a very poor prognosis. Current treatments for ATRT include resection of the tumor, followed by systemic chemotherapy and radiation therapy, which have toxic side effects for young children. Gene expression analyses of human ATRTs and normal brain samples indicate that ATRTs have aberrant expression of epigenetic markers including class I histone deacetylases (HDAC’s) and lysine demethylase (LSD1). Here, we investigate the effect of a small molecule epigenetic modulator known as Domatinostat (4SC-202), which inhibits both class I HDAC’s and Lysine Demethylase (LSD1), on ATRT cell survival and single cell heterogeneity. Our findings suggest that 4SC-202 is both cytotoxic and cytostatic to ATRT in 2D and 3D scaffold cell culture models and may target cancer stem cells. Single-cell RNA sequencing data from ATRT-06 spheroids treated with 4SC-202 have a reduced population of cells overexpressing stem cell-related genes, including SOX2. Flow cytometry and immunofluorescence on 3D ATRT-06 scaffold models support these results suggesting that 4SC-202 reduces expression of cancer stem cell markers SOX2, CD133, and FOXM1. Drug-induced changes to the systems biology landscape are also explored by multi-omics enrichment analyses. In summary, our data indicate that 4SC-202 has both cytotoxic and cytostatic effects on ATRT, targets specific cell sub-populations, including those with cancer stem-like features, and is an important potential cancer therapeutic to be investigated in vivo.

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4SC-202 as a Potential Treatment for the Pediatric Brain Tumor Medulloblastoma

Cited by 19 publications

References 22 publications

Biphasic regulation of tumorigenesis by PTK7 expression level in esophageal squamous cell carcinoma

Biphasic regulation of tumorigenesis by PTK7 expression level in esophageal squamous cell carcinoma

The HDAC Inhibitor Domatinostat Promotes Cell-Cycle Arrest, Induces Apoptosis, and Increases Immunogenicity of Merkel Cell Carcinoma Cells

Analysis of Dual Class I Histone Deacetylase and Lysine Demethylase Inhibitor Domatinostat (4SC-202) on Growth and Cellular and Genomic Landscape of Atypical Teratoid/Rhabdoid

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