18F-FLT Positron Emission Tomography (PET) is a Pharmacodynamic Marker for EWS-FLI1 Activity and Ewing Sarcoma

Osgood, Christy; Tantawy, Mohammed Noor; Maloney, Nichole; Madaj, Zachary; Peck, Anderson; Boguslawski, Elissa A.; Jess, Jennifer; Buck, Jason R.; Winn, Mary E.; Manning, H. Charles; Grohar, Patrick J.

doi:10.1038/srep33926

Cited by 8 publications

(7 citation statements)

References 33 publications

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“…Finally, this study highlights the need for the evaluation of target suppression in patients. We have ongoing efforts aimed at developing these correlative biomarkers for Ewing sarcoma [32]. The study was opened with the goal of obtaining tissue biopsies before and after drug treatment in adult patients with accessible disease.…”

Section: Discussionmentioning

confidence: 99%

A phase I/II trial and pharmacokinetic study of mithramycin in children and adults with refractory Ewing sarcoma and EWS–FLI1 fusion transcript

Grohar

Glod

Peer

et al. 2017

Cancer Chemother Pharmacol

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Section: Discussionmentioning

confidence: 99%

A phase I/II trial and pharmacokinetic study of mithramycin in children and adults with refractory Ewing sarcoma and EWS–FLI1 fusion transcript

Grohar

Glod

Peer

et al. 2017

Cancer Chemother Pharmacol

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“…Because irinotecan is known to impact transcription, we sought to determine whether the function of irinotecan in this combination is to improve the magnitude, penetrance, or duration of EWS-FLI1 suppression. We have previously shown that 18 F-FLT PET reflects EWS-FLI1 activity because EWS-FLI1 drives the expression of the proteins responsible for activity in Ewing cells, ENT1/ENT2 and TK1 (48).…”

Section: Trabectedin Requires Irinotecan To Improve Suppression Of Ewmentioning

confidence: 99%

Trabectedin Inhibits EWS-FLI1 and Evicts SWI/SNF from Chromatin in a Schedule-dependent Manner

Harlow

Chassé

Boguslawski

et al. 2019

Clinical Cancer Research

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Purpose: The successful clinical translation of compounds that target specific oncogenic transcription factors will require an understanding of the mechanism of target suppression to optimize the dose and schedule of administration. We have previously shown trabectedin reverses the gene signature of the EWS-FLI1 transcription factor. In this report, we establish the mechanism of suppression and use it to justify the reevaluation of this drug in the clinic in patients with Ewing sarcoma.Experimental Design: We demonstrate a novel epigenetic mechanism of trabectedin using biochemical fractionation and chromatin immunoprecipitation sequencing. We link the effect to drug schedule and EWS-FLI1 downstream target expression using confocal microscopy, qPCR, Western blot analysis, and cell viability assays. Finally, we quantitate target suppression within the three-dimensional architecture of the tumor in vivo using 18 F-FLT imaging.Results: Trabectedin evicts the SWI/SNF chromatinremodeling complex from chromatin and redistributes EWS-FLI1 in the nucleus leading to a marked increase in H3K27me3 and H3K9me3 at EWS-FLI1 target genes. These effects only occur at high concentrations of trabectedin leading to suppression of EWS-FLI1 target genes and a loss of cell viability. In vivo, low-dose irinotecan is required to improve the magnitude, penetrance, and duration of target suppression in the three-dimensional architecture of the tumor leading to differentiation of the Ewing sarcoma xenograft into benign mesenchymal tissue.Conclusions: These data provide the justification to evaluate trabectedin in the clinic on a short infusion schedule in combination with low-dose irinotecan with 18 F-FLT PET imaging in patients with Ewing sarcoma.

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“…23 In human tissues, FLI1 is abnormally expressed in some solid tumours, including Ewing sarcoma, breast cancer and astrocytoma. [24][25][26] In endothelial cells, FLI1 is a regulator of vessel maturation and stabilization via modulating expressions of genes involved in maintaining vascular homoeostasis and integrity. 27,28 However, a little attention has been directed to clarify the possible role of FLI1 in GECs and BTB permeability.…”

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confidence: 99%

Circular RNA USP1 regulates the permeability of blood‐tumour barrier via miR‐194‐5p/FLI1 axis

Gao

et al. 2019

J Cellular Molecular Medi

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Recent studies indicate circular RNAs are related to dysregulation of vascular endothelial cell function, yet the underlying mechanisms have remained elusive. Here, we characterized the functional role of circular RNA USP1 (circ‐USP1) in the regulation of the blood‐tumour barrier (BTB) permeability and the potential mechanisms. In the current study, the circ‐USP1 expressing level was up‐regulated in glioma cerebral microvascular endothelial cells (GECs) of the BTB model in vitro. Knockdown of circ‐USP1 disrupted the barrier integrity, increased its permeability as well as reduced tight junction‐related protein claudin‐5, occludin and ZO‐1 expressions in GECs. Bioinformatic prediction and luciferase assay indicated that circ‐USP1 bound to miR‐194‐5p and suppressed its activity. MiR‐194‐5p contributed to circ‐USP1 knockdown‐induced increase of BTB permeability via targeting and down‐regulating transcription factor FLI1. Furthermore, FLI1 regulated the expressions of claudin‐5, occludin and ZO‐1 in GECs through binding to their promoter regions. Single or combined treatment of circ‐USP1 and miR‐194‐5p effectively promoted anti‐tumour drug doxorubicin across BTB to induce apoptosis of glioma cells. Overall, this present study identified the crucial regulation of circ‐USP1 on BTB permeability via miR‐194‐5p/FLI1 axis‐mediated regulation of tight junction proteins, which might facilitate the development of therapeutics against human gliomas.

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18F-FLT Positron Emission Tomography (PET) is a Pharmacodynamic Marker for EWS-FLI1 Activity and Ewing Sarcoma

Cited by 8 publications

References 33 publications

A phase I/II trial and pharmacokinetic study of mithramycin in children and adults with refractory Ewing sarcoma and EWS–FLI1 fusion transcript

A phase I/II trial and pharmacokinetic study of mithramycin in children and adults with refractory Ewing sarcoma and EWS–FLI1 fusion transcript

Trabectedin Inhibits EWS-FLI1 and Evicts SWI/SNF from Chromatin in a Schedule-dependent Manner

Circular RNA USP1 regulates the permeability of blood‐tumour barrier via miR‐194‐5p/FLI1 axis

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