Review
Oncology
Helong Gong, Busheng Xue, Jinlong Ru, Guoqing Pei, Yan Li
Summary: Ewing sarcoma (EwS) is a rare and predominantly pediatric malignancy of bone and soft tissue in children and adolescents. The EWS-FLI1 oncogene acts as an aberrant transcription factor that drives the cellular transformation of EwS. Direct pharmacological targeting of EWS-FLI1 is difficult, but targeting the EWS-FLI1 protein complex or downstream pathways provides additional therapeutic options.
Article
Chemistry, Multidisciplinary
Siyuan Su, Jianfeng Chen, Yao Jiang, Ying Wang, Tamara Vital, Jiaming Zhang, Christian Laggner, Kong T. Nguyen, Zhichuan Zhu, Alex W. Prevatte, Natalie K. Barker, Laura E. Herring, Ian J. Davis, Pengda Liu
Summary: Chromosomal translocation leads to the formation of the EWS-FLI1 fusion oncogene in Ewing sarcoma, with SPOP identified as the E3 ligase and OTUD7A as the deubiquitinase regulating EWS-FLI1 protein stability. Targeting OTUD7A with the inhibitor 7Ai shows potential as a therapeutic strategy for Ewing sarcoma dependent on EWS-FLI1 and related fusions.
Article
Oncology
Shan Wang, Xiaofang Huo, Yiping Yang, Yingxi Mo, Rahul K. Kollipara, Ralf Kittler
Summary: The deubiquitinase USP9X stabilizes EWS-FLI1 protein expression in Ewing sarcoma, and its inhibitor WP1130 can rapidly degrade EWS-FLI1 and inhibit the growth of Ewing sarcoma cells and tumors.
Review
Biochemistry & Molecular Biology
Muhammad Yasir, Jinyoung Park, Wanjoo Chun
Summary: Despite their clonal origins, tumors evolve into complex communities with phenotypically different cell subpopulations. Ewing sarcoma, a highly aggressive malignancy primarily affecting adolescents, exhibits significant variations in transcriptional activity among tumors despite originating from a common driver mutation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Oncology
April A. Apfelbaum, Feinan Wu, Allegra G. Hawkins, Brian Magnuson, Jennifer A. Jime, Sean D. Taylor, Emma D. Wrenn, Olivia Waltner, Elise R. Pfaltzgraff, Jane Y. Song, Cody Hall, Deneen M. Wellik, Mats Ljungman, Scott N. Furlan, Russell J. H. Ryan, Jay F. Sarthy, Elizabeth R. Lawlor
Summary: This study reveals the regulatory role of HOXD13 in EWS::FLI1 transcriptional activity and its impact on the transition of Ewing sarcoma cells towards a mesenchymal state. The findings provide important insights into the progression mechanism of Ewing sarcoma.
CLINICAL CANCER RESEARCH
(2022)
Article
Oncology
Yu Wang, Hengtang Mai, Ying Yuan, Hairen Chen, Song Wu, Xiang Hu, Aixi Yu
Summary: Ewing sarcoma is an aggressive pediatric tumor with limited diagnostic tools. A near-infrared fluorescent probe targeting the specific fusion protein EWS-FLI1 was synthesized, showing promising results in identifying tumor boundaries and lymph node metastases in animal models. This probe has the potential for early diagnosis and surgical guidance of Ewing sarcoma through molecularly targeted NIR imaging.
MOLECULAR ONCOLOGY
(2021)
Review
Cell Biology
Maryne Dupuy, Francois Lamoureux, Mathilde Mullard, Anais Postec, Laura Regnier, Marc Baud'huin, Steven Georges, Benedicte Brounais-Le Royer, Benjamin Ory, Francoise Redini, Franck Verrecchia
Summary: Ewing sarcoma (ES) is the second most common primary malignant bone tumor in children, adolescents, and young adults in Europe, with a survival rate of 70% for localized forms using conventional treatment. However, resistance to chemotherapy and pulmonary metastases greatly reduce the survival rate. ES is characterized by a chromosomal translocation that leads to the fusion protein EWS-FLI1, which plays a crucial role in the development of ES. This review provides an overview of ES from a clinical and biological perspective.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2023)
Article
Oncology
Alessandra De Feo, Laura Pazzaglia, Lisa Ciuffarin, Fabio Mangiagli, Michela Pasello, Elisa Simonetti, Evelin Pellegrini, Cristina Ferrari, Giuseppe Bianchi, Benedetta Spazzoli, Katia Scotlandi
Summary: Ewing's sarcoma, a common pediatric bone tumor, relies on genetic and epigenetic alterations that induce gene expression reprogramming. The study identifies miR-214-3p as a common mediator of EWS-FLI1 and CD99, and its restoration inhibits tumor cell growth and migration by repressing HMGA1 expression.
Article
Biochemistry & Molecular Biology
Hyewon Park, Haeyoung Kim, Victoria Hassebroek, Yoshiaki Azuma, Chad Slawson, Mizuki Azuma
Summary: The study demonstrates that EWSR1/FLI1 induces aneuploidy by interfering with the localization of Aurora B kinase, with phosphorylation of Thr 79 being critical for this process.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Oncology
Gloria Pedot, Joana Graca Marques, Philip P. Ambuhl, Marco Wachtel, Stephanie Kasper, Quy A. Ngo, Felix K. Niggli, Beat W. Schaefer
Summary: Transcription factor EWS-FLI1 is an oncogenic protein that lacks enzymatic activity and has been considered undruggable. Through a high-throughput drug screen and a global protein stability approach, a compound called fimepinostat was identified as a potential candidate to destabilize EWS-FLI1 protein and reduce Ewing sarcoma tumor progression. This study demonstrates the effectiveness of combining drug screening and protein stability analysis in identifying drugs that can modulate the stability of EWS-FLI1 and paves the way for the development of new therapeutic strategies.
Review
Oncology
Balaji Ramachandran, Thangarajan Rajkumar, Gopal Gopisetty
Summary: EWS-FLI1 is considered a master regulator of Ewing sarcoma oncogenesis, but targeted therapeutic inhibitors are currently lacking. Past attempts to develop specific models or in vivo systems have seen limited success, and accelerating the establishment of these models may help speed up the development of therapeutic inhibitors.
AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH
(2021)
Article
Oncology
Charlie Buchou, Karine Laud-Duval, Wietske van der Ent, Sandrine Grossetete, Sakina Zaidi, Geraldine Gentric, Maxime Corbe, Kevin Muller, Elaine Del Nery, Didier Surdez, Olivier Delattre
Summary: The study identified the MVA pathway as a major dependency in Ewing sarcoma, and statins as a potential new therapeutic agent for the treatment of this disease.
Article
Biochemistry & Molecular Biology
Daniel J. Garcia-Dominguez, Nabil Hajji, Sara Sanchez-Molina, Elisabet Figuerola-Bou, Rocio M. de Pablos, Ana M. Espinosa-Oliva, Eduardo Andres-Leon, Laura Carmen Terron-Camero, Rocio Flores-Campos, Guillem Pascual-Pasto, Maria Jose Robles, Angel M. Carcaboso, Jaume Mora, Enrique de Alava, Lourdes Hontecillas-Prieto, Isidro Machado, Antonio Llombart-Bosch, Giovanna Magagnoli, Katia Scotlandi
Summary: The study reveals that HDAC6 plays a regulatory role in EWS, and selective inhibition of HDAC6 can reduce the oncogenic functions of EWSR1-FLI1. High expression of HDAC6 is associated with poor prognosis in EWS patients, and a combination treatment of HDAC6 and doxorubicin significantly inhibits tumor growth in EWS models.
Review
Oncology
Mingli Li, Chunwei Chen
Summary: Ewing sarcoma (EwS) is a common type of bone and soft tissue cancer that primarily affects children and adolescents. The current treatment approach for EwS patients involves a combination of surgery, radiation, and chemotherapy. However, little progress has been made in the treatment of patients with metastatic or relapsed diseases. Furthermore, the survival rates for localized cases are relatively low, and the development of metastatic tumors significantly reduces the five-year survival rates. Therefore, understanding the regulatory mechanism of EwS tumor metastasis is crucial for developing effective treatment strategies. This review discusses the molecular signatures and heterogeneity associated with EwS metastasis.
Article
Oncology
Saint T. Cervera, Carlos Rodriguez-Martin, Enrique Fernandez-Tabanera, Raquel M. Melero-Fernandez de Mera, Matias Morin, Sergio Fernandez-Penalver, Maria Iranzo-Martinez, Jorge Amhih-Cardenas, Laura Garcia-Garcia, Laura Gonzalez-Gonzalez, Miguel Angel Moreno-Pelayo, Javier Alonso
Summary: Ewing sarcoma is an aggressive bone cancer affecting children and young adults, characterized by chromosomal translocations producing chimeric oncogenic transcription factors. In this study, genetic inactivation of the EWSR1-FLI1 oncogene using CRISPR/Cas9 technology in Ewing sarcoma cells effectively blocked cell proliferation and induced a senescence phenotype. This suggests that complete inactivation of EWSR1-FLI1 at the cellular level could be a promising therapeutic approach in the future.