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Drug screening identifies tazarotene and bexarotene as therapeutic agents in Multiple Sulfatase Deficiency

ABSTRACT: Drug screening identifies tazarotene and bexarotene as therapeutic agents in Multiple Sulfatase Deficiency

PROVIDER: PRJNA846323 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19552700_1.fastq.gz	Fastqsanger.gz
	SRR19552700_2.fastq.gz	Fastqsanger.gz
	SRR19552701_1.fastq.gz	Fastqsanger.gz
	SRR19552701_2.fastq.gz	Fastqsanger.gz
	SRR19552702_1.fastq.gz	Fastqsanger.gz

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Drug screening identifies tazarotene and bexarotene as therapeutic agents in Multiple Sulfatase Deficiency II

Project description:Drug screening identifies tazarotene and bexarotene as therapeutic agents in Multiple Sulfatase Deficiency II

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Drug screening identifies tazarotene and bexarotene as therapeutic agents in Multiple Sulfatase Deficiency II

Project description:We analysed differences in gene expression upon treatment of MSD patient fibroblast lines and control fibroblast lines with tazarotene and bexarotene or DMSO control (untreated condition)

2022-10-31 | GSE205556 | GEO

Drug screening identifies tazarotene and bexarotene as therapeutic agents in multiple sulfatase deficiency.

Project description:Multiple sulfatase deficiency (MSD, MIM #272200) results from pathogenic variants in the SUMF1 gene that impair proper function of the formylglycine-generating enzyme (FGE). FGE is essential for the posttranslational activation of cellular sulfatases. MSD patients display reduced or absent sulfatase activities and, as a result, clinical signs of single sulfatase disorders in a unique combination. Up to date therapeutic options for MSD are limited and mostly palliative. We performed a screen of FDA-approved drugs using immortalized MSD patient fibroblasts. Recovery of arylsulfatase A activity served as the primary readout. Subsequent analysis confirmed that treatment of primary MSD fibroblasts with tazarotene and bexarotene, two retinoids, led to a correction of MSD pathophysiology. Upon treatment, sulfatase activities increased in a dose- and time-dependent manner, reduced glycosaminoglycan content decreased and lysosomal position and size normalized. Treatment of MSD patient derived induced pluripotent stem cells (iPSC) differentiated into neuronal progenitor cells (NPC) resulted in a positive treatment response. Tazarotene and bexarotene act to ultimately increase the stability of FGE variants. The results lay the basis for future research on the development of a first therapeutic option for MSD patients.

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Drug screening identifies tazarotene and bexarotene as therapeutic agents in Multiple Sulfatase Deficiency

Project description:We analysed differences in gene expression upon treatment of MSD patient fibroblast lines with either tazarotene or adapalene and DMSO control (untreated condition)

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Drug screening identifies tazarotene and bexarotene as therapeutic agents in Multiple Sulfatase Deficiency

Project description:Multiple Sulfatase Deficiency (MSD, MIM #272200) results from pathogenic variants in the SUMF1 gene that impair proper function of the formylglycine-generating enzyme (FGE). FGE is essential for the posttranslational activation of cellular sulfatases. MSD patients display reduced sulfatase activities and clinical signs of single sulfatase disorders in a unique combination. Up to date therapeutic options for MSD are mostly palliative. We performed a screen of FDA-approved drugs using immortalised MSD patient fibroblasts. Recovery of arylsulfatase A activity served as the primary readout. Subsequent analysis confirmed that treatment of MSD fibroblasts with tazarotene and bexarotene led to a correction of MSD pathophysiology. Upon treatment, sulfatase activities increased in a dose- and time-dependent manner, glycosaminoglycan content decreased and lysosomal position and size normalized. Treatment of MSD patient derived induced pluripotent stem cells (iPSC) differentiated into neuronal progenitor cells (NPC) resulted in a positive treatment response. Tazarotene and bexarotene act to ultimately increase the stability of FGE variants. The results lay the basis for future research on the development of a first therapeutic option for MSD patients.

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Differentiation of Mesenchymal Glioblastoma Multiform by Bexarotene

Project description:Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumor. Differentiation can attenuate or block tumor growth; thus, phenotypic screenings were performed to search for drugs inducing differentiational morphological changes in mesenchymal recurrent GBM, a temozolomide (TMZ)-resistant brain cancer. Bexarotene, a selective retinoid X receptor agonist, showed strong inhibition of neurospheroidal colony formation and migration of cultured GBM stem cells. Bexarotene decreased nestin expression and significantly increased GFAP expression. Gene expression changes by bexarotene and all-trans retinoic acid (ATRA), a well-known differentiation inducer, were compared. Both drugs largely altered the gene expression pattern into a tumor-ameliorating direction. These drugs increased the gene expression levels of Krüppel-like factor 9 (KLF9), regulator of G-protein signaling 4 (RGS4), growth differentiation factor 15 (GDF15), angiopoietin-like protein 4 (ANGPTL4), and lowered the level of chemokine receptor type 4 (CXCR4). Both drugs also induced a potential oncogene, transglutaminase 2 (TG2), but the fold-change induced by bexarotene was considerably lesser than that by ATRA. Consistently, the TG2 activity in GBM was elevated several folds by ATRA. Because TG2 upregulation is correlated with tumor transformation and resistance, it is important to control its overexpression. Bexarotene does not upregulate TG2 as much as ATRA, and bexarotene showed in vivo tumoricidal effects in a GBM xenograft mouse model. Thus, these findings strongly suggest that bexarotene is more beneficial than ATRA and should be considered as a differentiation therapeutic agent for mesenchymal GBM.

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Inhibition of the integrin alpha-V beta-3 reverts the paradoxical effect of levothyroxine replacement during bexarotene therapy in cutaneous T-cell lymphoma

Project description:Bexarotene is a specific RXR agonist that has been used for the treatment of cutaneous T-cell lymphoma (CTCL). The mechanism of action is pleiotropic but impacts directly on CTCL cell proliferation, chemotaxis and apoptosis, and indirectly on lymphoma immunity. Bexarotene causes hypothyroidism in more than 90% of patients thus requiring the concomitant administration of levothyroxine. Hereon we investigated the consequence of levothyroxine administration to the antineoplastic effect of bexarotene in CTCL. We found that bexarotene induces transcriptional and biological changes in CTCL cells related to decreased cell proliferation and chemotaxis, as well as increased proliferation and interferon response. Although lack of levothyroxine supplementation during bexarotene treatment increased apoptosis and decreased cell proliferation of CTCL cells in vitro and in vivo, it also decreased the lymphoma immunity. Since levothyroxine activates both the ubiquitous TRA nuclear receptor and the more restricted integrin V3 membrane receptor that is overexpressed in CTCL cells, we investigated their role in bexarotene treatment. We demonstrated that genetic and pharmacologic inhibition of the integrin V3 receptors resulted in improved bexarotene-induced effects on apoptosis, cell proliferation and chemotaxis while maintaining the lymphoma immunity. Our results provide a mechanistic rationale for evaluating the addition of the integrin V3 inhibitor cilengitide to CTCL therapeutic regimens that are based on bexarotene and levothyroxine supplementation.

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DNA demethylating agents represent a therapeutic opportunity for synovial sarcoma

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