scholarly journals Ewing's Sarcoma: Development of RNA Interference-Based Therapy for Advanced Disease

ISRN Oncology ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Olivia Simmons ◽  
Phillip B. Maples ◽  
Neil Senzer ◽  
John Nemunaitis
Keyword(s):  
Rna Interference ◽  
Ewing’S Sarcoma ◽  
Ewing's Sarcoma ◽  
Advanced Disease ◽  
Chromosomal Translocation ◽  
Transcription Factor Gene ◽  
Factor Gene ◽  
Systemic Rnai ◽  
Ets Transcription Factor ◽  
Target Sequences

Ewing's sarcoma tumors are associated with chromosomal translocation between the EWS gene and the ETS transcription factor gene. These unique target sequences provide opportunity for RNA interference(i)-based therapy. A summary of RNAi mechanism and therapeutically designed products including siRNA, shRNA and bi-shRNA are described. Comparison is made between each of these approaches. Systemic RNAi-based therapy, however, requires protected delivery to the Ewing's sarcoma tumor site for activity. Delivery systems which have been most effective in preclinical and clinical testing are reviewed, followed by preclinical assessment of various silencing strategies with demonstration of effectiveness to EWS/FLI-1 target sequences. It is concluded that RNAi-based therapeutics may have testable and achievable activity in management of Ewing's sarcoma.

scholarly journals Primary Ewing’s Sarcoma of the Sinonasal Tract: A Case Report

2017 ◽  
Vol 10 (1) ◽  
pp. 91-97 ◽  
Author(s):  
Tomoharu Suzuki ◽  
Ryuji Yasumatsu ◽  
Torahiko Nakashima ◽  
Shuji Arita ◽  
Hidetaka Yamamoto ◽  
...  
Keyword(s):  
Ewing’S Sarcoma ◽  
Ewing's Sarcoma ◽  
Maxillary Antrum ◽  
Chromosomal Translocation ◽  
Microscopic Analysis ◽  
Complete Removal ◽  
Mri Scans ◽  
History Of ◽  
Mitotic Figures ◽  
Contiguous Spread

A 23-year-old male presented with a 3-month history of left purulent rhinorrhea, progressive nasal obstruction, and intermittent epistaxis. A fiberoptic examination revealed a large vascular polypoid mass completely filling the left nasal cavity. CT and MRI scans showed a large hypervascular mass involving the left nasal airway, maxillary antrum, and the anterior ethmoid cells. There was no bony erosion or contiguous spread, and the remaining sinuses, orbit, and cranial fossa were uninvolved. The patient underwent complete removal of the mass via an external lateral rhinotomy approach. The soft mass was large and vascular. A microscopic analysis revealed an undifferentiated tumor consisting of a solid sheet of small, round blue cells. Mitotic figures were also present. Immunohistochemically, the tumor cells were strongly positive for CD99. Molecular studies using a PCR confirmed the chromosomal translocation of FLI1 (exon 6). These findings were considered diagnostic for Ewing’s sarcoma. Postoperatively, the patient was treated with combined chemotherapy and radiotherapy. Adjuvant chemotherapy consisting of vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide (total: 7 cycles) was commenced. He also received radiation therapy for local control (total dose: 50.4 Gy). The patient is currently alive without any evidence of recurrence or metastasis.

The Novel Epithelial-Specific Ets Transcription Factor Gene ESX Maps to Human Chromosome 1q32.1

Genomics ◽  
1997 ◽  
Vol 45 (2) ◽  
pp. 456-457 ◽  
Author(s):  
Peter Oettgen ◽  
Kenneth C. Carter ◽  
Meena Augustus ◽  
Marcello Barcinski ◽  
Jay Boltax ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Human Chromosome ◽  
The Novel ◽  
Transcription Factor Gene ◽  
Factor Gene ◽  
Ets Transcription Factor

scholarly journals Cell Cycle Deregulation in Ewing's Sarcoma Pathogenesis

Sarcoma ◽  
2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Ashley A. Kowalewski ◽  
R. Lor Randall ◽  
Stephen L. Lessnick
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Target Genes ◽  
Ewing’S Sarcoma ◽  
Ewing's Sarcoma ◽  
Cell Cycle Control ◽  
Chromosomal Translocation ◽  
Published Data ◽  
Pediatric Tumor ◽  
Cell Cycle Deregulation

Ewing's sarcoma is a highly aggressive pediatric tumor of bone that usually contains the characteristic chromosomal translocation t(11;22)(q24;q12). This translocation encodes the oncogenic fusion protein EWS/FLI, which acts as an aberrant transcription factor to deregulate target genes necessary for oncogenesis. One key feature of oncogenic transformation is dysregulation of cell cycle control. It is therefore likely that EWS/FLI and other cooperating mutations in Ewing's sarcoma modulate the cell cycle to facilitate tumorigenesis. This paper will summarize current published data associated with deregulation of the cell cycle in Ewing's sarcoma and highlight important questions that remain to be answered.

scholarly journals Extraskeletal Ewing's sarcoma in a great toe of a young boy

2007 ◽  
Vol 15 (3) ◽  
pp. 165-168 ◽  
Author(s):  
Tatiana Karine Simon Cypel ◽  
Benjamin Meilik ◽  
Ronald Melvin Zuker
Keyword(s):  
Differential Diagnosis ◽  
Clinical Case ◽  
Ewing’S Sarcoma ◽  
Histological Analysis ◽  
Ewing's Sarcoma ◽  
Malignant Neoplasm ◽  
Chromosomal Translocation ◽  
Round Cell ◽  
Great Toe ◽  
Extraskeletal Ewing’S Sarcoma

Extraskeletal Ewing's sarcoma (EES) is a rare, soft tissue, malignant neoplasm histologically similar to skeletal Ewing's sarcoma. It occurs mainly in adolescents and young adults, and affects extremities in 36% of cases and central locations (commonly paravertebral regions) in the remainder. The differential diagnosis includes other small, blue, round cell tumours. A clinical case of EES involving a great toe in a young boy is reported. EES diagnosis was confirmed by features of histological analysis and immunohistochemistry, and by the presence of the t(11;22) chromosomal translocation.

scholarly journals γ-Glutamyl transpeptidase expression in Ewing's sarcoma cells:up-regulation by interferons

2002 ◽  
Vol 364 (3) ◽  
pp. 719-724 ◽  
Author(s):  
Lena BOUMAN ◽  
Josiane SANCÉAU ◽  
Dany ROUILLARD ◽  
Brigitte BAUVOIS
Keyword(s):  
Cell Lines ◽  
Ewing’S Sarcoma ◽  
Ewing's Sarcoma ◽  
Fusion Gene ◽  
Chromosomal Translocation ◽  
Cellular Transformation ◽  
Enzymic Activity ◽  
Type I ◽  
Chromosomal Breaks ◽  
Glutamyl Transpeptidase

The genetic hallmark of Ewing's sarcoma family of tumours (ET) is the presence of the translocation t(11;22)(q24;q12), which creates the ET fusion gene, leading to cellular transformation. Five human γ-glutamyl transpeptidase (γ-GT) genes are located near the chromosomal translocation in ET. γ-GT is a major enzyme involved in glutathione homoeostasis. Five human cell lines representative of primary or metastatic tumours were investigated to study whether γ-GT alterations could occur at the chromosomal breaks and rearrangements in ET. As shown by enzymic assays and FACS analyses, all ET cell lines consistently expressed a functional γ-GT which however did not discriminate steps of ET progression. As shown previously [Sancéau, Hiscott, Delattre and Wietzerbin (2000) Oncogene 19, 3372–3383], ET cells respond to the antiproliferative effects of interferons (IFNs) type I (α and β) and to a much less degree to IFN type II (γ). IFN-α and -β arrested cells in the S-phase of the cell cycle. We found an enhancement of γ-GT mRNA species with IFN-α and -β by reverse transcriptase—PCR analyses. This is reflected by up-regulation of γ-GT protein, which coincides with the increase in γ-GT-specific enzymic activity. Similarly, IFNs up-regulate the levels of γ-GT in another IFN-responsive B cell line. Whether this up-regulation of γ-GT by IFNs is of physiological relevance to cell behaviour remains to be studied.

scholarly journals Identification of a New Transcriptional Co-Regulator of STEAP1 in Ewing’s Sarcoma

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1300
Author(s):  
Fatu Badiane Markey ◽  
Brigette Romero ◽  
Vijay Parashar ◽  
Mona Batish
Keyword(s):  
Transcription Factor ◽  
Single Molecule ◽  
Drug Targets ◽  
Ewing’S Sarcoma ◽  
Ewing's Sarcoma ◽  
Transmembrane Protein ◽  
Chromosomal Translocation ◽  
Therapeutic Interventions ◽  
Tumor Invasiveness ◽  
Novel Drug

Ewing’s sarcoma (ES) is caused by a chromosomal translocation leading to the formation of the fused EWSFLI1 gene, which codes for an aberrant transcription factor EWSFLI1. The transcriptional targets of EWSFLI1 have been viewed as promising and novel drug targets in the treatment of ES. One such target is six transmembrane epithelial antigen of the prostate 1 (STEAP1), a transmembrane protein that is upregulated by EWSFLI1 in ES. STEAP1 is a hallmark of tumor invasiveness and an indicator of tumor responsiveness to therapy. EWSFLI1 binds to the STEAP1 promoter region, but the mechanism of action by which it upregulates STEAP1 expression in ES is not entirely understood. Upon analysis of the STEAP1 promoter, we predicted two binding sites for NKX2.2, another crucial transcription factor involved in ES pathogenesis. We confirmed the interaction of NKX2.2 with the STEAP1 promoter using chromatin immunoprecipitation (ChIP) analysis. We used single-molecule RNA imaging, biochemical, and genetic studies to identify the novel role of NKX2.2 in regulating STEAP1 expression in ES. Our results show that NKX2.2 is a co-regulator of STEAP1 expression and functions by interacting with the STEAP1 promoter at sites proximal to the reported EWSFLI1 sites. The co-operative interaction of NKX2.2 with EWSFLI1 in regulating STEAP1 holds potential as a new target for therapeutic interventions for ES.

scholarly journals Identification of target genes for the Ewing's sarcoma EWS/FLI fusion protein by representational difference analysis.

1995 ◽  
Vol 15 (8) ◽  
pp. 4623-4630 ◽  
Author(s):  
B S Braun ◽  
R Frieden ◽  
S L Lessnick ◽  
W A May ◽  
C T Denny
Keyword(s):  
Target Genes ◽  
Ewing’S Sarcoma ◽  
Ewing's Sarcoma ◽  
Germ Line ◽  
Fusion Gene ◽  
Chromosomal Translocation ◽  
Representational Difference Analysis ◽  
Difference Analysis ◽  
Broad Array ◽  
Direct Target Gene

The EWS/FLI-1 fusion gene results from the 11;22 chromosomal translocation in Ewing's sarcoma. The product of the gene is one of a growing number of structurally altered transcription factors implicated in oncogenesis. We have employed a subtractive cloning strategy of representational difference analysis in conjunction with a model transformation system to identify genes transcribed in response to EWS/FLI. We have characterized eight transcripts that are dependent on EWS/FLI for expression and two transcripts that are repressed in response to EWS/FLI. Three of the former were identified by sequence analysis as stromelysin 1, a murine homolog of cytochrome P-450 F1 and cytokeratin 15. Stromelysin 1 is induced rapidly after expression of EWS/FLI, suggesting that the stromelysin 1 gene may be a direct target gene of EWS/FLI. These results demonstrate that expression of EWS/FLI leads to significant changes in the transcription of specific genes and that these effects are at least partially distinct from those caused by expression of germ line FLI-1. The representational difference analysis technique can potentially be applied to investigate transformation pathways activated by a broad array of genes in different tumor systems.

scholarly journals Targeting of EWS/FLI-1 by RNA interference attenuates the tumor phenotype of Ewing's sarcoma cells in vitro

2004 ◽  
Vol 22 (4) ◽  
pp. 910-917 ◽  
Author(s):  
Howard A. Chansky ◽  
Fariba Barahmand-pour ◽  
Qi Mei ◽  
Waqqar Kahn-Farooqi ◽  
Anna Zielinska-Kwiatkowska ◽  
...  
Keyword(s):  
Rna Interference ◽  
Ewing’S Sarcoma ◽  
Ewing's Sarcoma ◽  
Ewing's Sarcoma Cells ◽  
Tumor Phenotype ◽  
Sarcoma Cells
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