Phase II trial of gemcitabine and nab‐paclitaxel in patients with recurrent Ewing sarcoma: A report from the National Pediatric Cancer Foundation

Oesterheld, Javier; Reed, Damon R.; Setty, Bhuvana; Isakoff, Michael S.; Thompson, Patrick A.; Yin, Hong; Hayashi, Masanori; Loeb, David M.; Smith, Tamara; Makanji, Rikesh; Fridley, Brooke L.; Wagner, Lars M.

doi:10.1002/pbc.28370

Cited by 19 publications

(13 citation statements)

References 32 publications

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“…Gemcitabine has been clinically used mainly for treatment of otherwise chemotherapy-refractory EwS (21). Unfortunately, gemcitabine is only effective in a subset of EwS patients and in most patients only for a short period of time (21,34). These clinical observations align with our findings of a rapidly acquired resistance toward gemcitabine in the A-673 EwS cell line.…”

Section: Discussionsupporting

confidence: 87%

“…Generally, the activity of RNR can be blocked by inhibiting RRM1 using a RRM1-specific inhibitor such as gemcitabine, or by RRM2-specific inhibitors such as hydroxyurea or a more potent drug triapine (alias 3-AP) (14, 20). Gemcitabine is used in conjunction with other antitumor agents such as taxanes for palliative treatments of EwS patients (21), and earlier reports have shown antineoplastic effects of gemcitabine in combination with CHEK1-inhibitors in short-term preclinical models (19). Yet, many EwS patients seem to rapidly develop a relative resistance toward gemcitabine (21).…”

Section: Resultsmentioning

confidence: 99%

“…Gemcitabine is used in conjunction with other antitumor agents such as taxanes for palliative treatments of EwS patients (21), and earlier reports have shown antineoplastic effects of gemcitabine in combination with CHEK1-inhibitors in short-term preclinical models (19). Yet, many EwS patients seem to rapidly develop a relative resistance toward gemcitabine (21). In support of this observation, we found that long-term treatment of the EwS cell lines with ascending doses of either doxorubicin (A-673, ES7, EW-7, TC-71), gemcitabine (A-673, ES7, TC-71) or triapine (A-673) led to acquisition of relative resistance phenotypes in vitro ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In our study, we extended this research and also pointed out issues of chemoresistance. Gemcitabine has been clinically used mainly for treatment of otherwise chemotherapy-refractory EwS (21). Unfortunately, gemcitabine is only effective in a subset of EwS patients and in most patients only for a short period of time (21, 34).…”

Section: Discussionmentioning

confidence: 99%

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Translational evidence for RRM2 as a prognostic biomarker and therapeutic target in Ewing sarcoma

Ohmura

Marchetto²,

Orth³

et al. 2021

Preprint

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Purpose: Ewing sarcoma (EwS) is a highly aggressive bone- or soft tissue-associated malignancy mostly affecting children, adolescents, and young adults. Although multimodal therapies have strongly improved patients′ overall survival over the past decades, the development of prognostic biomarkers for risk-based patient stratification and more effective therapies with less adverse effects is stagnating. Thus, new personalized medicine approaches are urgently required. Experimental design: Gene expression data of EwS and normal tissues were crossed with survival data to identify highly overexpressed, prognostically relevant, and actionable potential targets. RNA-interference and dose-response assays as well as tissue-microarray analyses were carried out to explore the functional role and druggability of a prominent candidate gene in vitro and in vivo, and to validate its suitability as a prognostic biomarker. Results: Employing a multilayered screening approach, we discover ribonucleotide reductase regulatory subunit M2 (RRM2) as a promising therapeutic target and prognostic biomarker in EwS. Through analysis of two independent EwS patient cohorts, we show that RRM2 mRNA and protein overexpression is associated with an aggressive clinical phenotype and poor patients′ overall survival. In agreement, RRM2 silencing as well as pharmacological inhibition by the specific inhibitor triapine (3-AP) significantly reduces EwS growth in vitro and in vivo. Furthermore, we present evidence that pharmacological RRM2 inhibition by triapine can overcome chemoresistance against doxorubicin or gemcitabine, and synergize with cell cycle checkpoint inhibitors (CHEK1 or WEE1). Conclusions: Based on the aggressive phenotype mediated by and the druggability of RRM2 our results provide a translational rationale for exploiting RRM2 as a novel therapeutic target in EwS and prompt further clinical investigations.

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Section: Discussionsupporting

confidence: 87%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Translational evidence for RRM2 as a prognostic biomarker and therapeutic target in Ewing sarcoma

Ohmura

Marchetto²,

Orth³

et al. 2021

Preprint

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“…At present, optimal treatment of ES emphasizes multimodal therapy [7][8][9]. Chemotherapy is an efficient treatment for ES, and it significantly improves the 5-year overall survival (OS) rate [10,11]. However, due to the lack of early efficient diagnosis, the high recurrence rate and distant metastasis of patients with ES lead to a poor prognosis [12], and the prognosis of patients with ES is not optimistic.…”

Section: Introductionmentioning

confidence: 99%

Bioinformatics Analysis of ZBTB16 as a Prognostic Marker for Ewing’s Sarcoma

Ding

Qiu

et al. 2021

BioMed Research International

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Objective. The purpose of this study is to identify novel biomarkers for the prognosis of Ewing’s sarcoma based on bioinformatics analysis. Methods. The GSE63157 and GSE17679 datasets contain patient and healthy control microarray data that were downloaded from the Gene Expression Omnibus (GEO) database and analyzed through R language software to obtain differentially expressed genes (DEGs). Firstly, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment, protein-protein interaction (PPI) networks, and Cytoscape Molecular Complex Detection (MCODE) plug-in were then used to compute the highest scores of the module. After survival analysis, the hub genes were lastly obtained from the two module genes. Results. A total of 1181 DEGs were identified from the two GSEs. Through MCODE and survival analysis, we obtain 53 DEGs from the module and 29 overall survival- (OS-) related genes. ZBTB16 was the only downregulated gene after Venn diagrams. Survival analysis indicates that there was a significant correlation between the high expression of ZBTB16 and the OS of Ewing’s sarcoma (ES), and the low expression group had an unfavorable OS when compared to the high expression group. Conclusions. High expression of ZBTB16 may serve as a predictor biomarker of poor prognosis in ES patients.

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USP12 promotes nonsmall cell lung cancer progression through deubiquitinating and stabilizing RRM2

Chen

Xue

Liu

et al. 2023

Molecular Carcinogenesis

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RRM2 is the catalytic subunit of ribonucleotide reductase (RNR), which catalyzes de novo synthesis of deoxyribonucleotide triphosphates (dNTPs) and plays critical roles in cancer cell proliferation. RRM2 protein level is controlled by ubiquitination mediated protein degradation system; however, its deubiquitinase has not been identified yet. Here we showed that ubiquitin‐specific peptidase 12 (USP12) directly interacts with and deubiquitinates RRM2 in non‐small cell lung cancer (NSCLC) cells. Knockdown of USP12 causes DNA replication stress and retards tumor growth in vivo and in vitro. Meanwhile, USP12 protein levels were positively correlated to RRM2 protein levels in human NSCLC tissues. In addition, high expression of USP12 was associated with poor prognosis in NSCLC patients. Therefore, our study reveals that USP12 is a RRM2 regulator and targeting USP12 could be considered as a potential therapeutical strategy for NSCLC treatment.

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Phase II trial of gemcitabine and nab‐paclitaxel in patients with recurrent Ewing sarcoma: A report from the National Pediatric Cancer Foundation

Cited by 19 publications

References 32 publications

Translational evidence for RRM2 as a prognostic biomarker and therapeutic target in Ewing sarcoma

Translational evidence for RRM2 as a prognostic biomarker and therapeutic target in Ewing sarcoma

Bioinformatics Analysis of ZBTB16 as a Prognostic Marker for Ewing’s Sarcoma

USP12 promotes nonsmall cell lung cancer progression through deubiquitinating and stabilizing RRM2

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