RETRACTED: Inhibition of HDACs reduces Ewing sarcoma tumor growth through EWS-FLI1 protein destabilization

Pedot, Gloria; Marques, Joana G.; Ambühl, Philip P.; Wachtel, Marco; Kasper, Stephanie; Ngo, Quy A.; Niggli, Felix; Schäfer, Beat W.

doi:10.1016/j.neo.2022.100784

Cited by 3 publications

(5 citation statements)

References 54 publications

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“…Fimepinostat greatly reduced the amount of fusion protein, decreased the viability of several Ewing sarcoma cell lines and PDX primary cells, and delayed tumor growth in a xenograft mouse model, while not significantly affecting healthy cells. They demonstrated that EWSR1-FLI1 protein levels were mainly regulated by the HDAC activity of Fimepinostat [97].…”

Section: Combining Targeted Drugs With Protein Degradationmentioning

confidence: 99%

“…HDACi acted synergistically with the EED inhibitor A-395 and together inhibited tumor growth of Ewing sarcoma xenografts [91]. Similarly, the dual HDAC and phosphatidylinositol 3-kinase (PI3K) inhibitor Fimepinostat can thus also provide simultaneous and sustained inhibition of multiple oncogenic pathways in Ewing sarcoma and reduce EWSR1-FLI1 levels and transcriptional activity [97]. Inhibition of HDAC activity largely affects Ewing sarcoma cell proliferation and survival, alone or in combination with DNA-damaging agents, through a variety of pathways that include induction of apoptosis, cell cycle arrest, and prevention of tumor invasion and metastasis [130][131][132][133].…”

Section: Inhibition Of Key Players Of the Fusion-positive Interactomementioning

confidence: 99%

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Drug Targeting of Chromosomal Translocations in Fusion-Positive Sarcoma

Richter¹

2023

Bone Tumours - A Comprehensive Review of Selected Topics

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Sarcomas are heterogeneous cancers of bone or soft tissue. They occur in children, adolescents, and young adults (AYAs). Herein, the subgroup of fusion-positive (FP) sarcomas is characterized by chromosomal rearrangements generating pathognomonic fusion transcripts and oncoproteins. In Ewing sarcoma (EwS), FP-rhabdomyosarcomas (FP-RMS) and synovial sarcomas (SyS), the most common and aggressive forms of sarcomas in childhood and adolescence, the oncogenic rearrangements involve transcription cofactors such as by FET-ETS, PAX3/7-FOXO1 or SS18-SSX fusion oncogenes in EwS, FP-RMS, or SyS, respectively causing widespread epigenetic rewiring and aberrant gene expression. Regardless of these translocations, few recurrent mutations are observed in these sarcomas that may contribute to disease; thus, it is of particular interest to consider the consequences of these translocations for tumor development. Results of current research examining the disease, analyzing, and classifying the role of associated rearrangements of chromatin, and investigating possibilities for tumor-specific intervention such as blocking the transcriptional activity of the fusion protein, or the processes caused by this activity are summarized here and some resulting therapeutic opportunities are presented.

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Section: Combining Targeted Drugs With Protein Degradationmentioning

confidence: 99%

Section: Inhibition Of Key Players Of the Fusion-positive Interactomementioning

confidence: 99%

Drug Targeting of Chromosomal Translocations in Fusion-Positive Sarcoma

Richter¹

2023

Bone Tumours - A Comprehensive Review of Selected Topics

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“…Due to the reliance of EWS::FLI1 on chromatin remodeling complexes, there is great interest in targeting Ewing sarcoma and the fusion specifically using epigenetic drugs including agents that inhibit HDACs (HDACi) (149), bromodomain proteins (BETi) (73, 150-152), LSD1 (LSD1i) (49, 72), and KDM3A (JIB-04) (153). Use of HDACi in vitro and in vivo inhibits Ewing sarcoma viability, proliferation, and tumor growth (154)(155)(156). HDACi can directly alter expression of the fusion protein (58, 155,156) and indirectly affect transcriptional function by reactivating expression of repressed target genes (37,154,155).…”

Section: Cytotoxic Agents and Small Molecules Can Inhibit Ews::fli1 A...mentioning

confidence: 99%

“…Use of HDACi in vitro and in vivo inhibits Ewing sarcoma viability, proliferation, and tumor growth ( 154 – 156 ). HDACi can directly alter expression of the fusion protein ( 58 , 155 , 156 ) and indirectly affect transcriptional function by reactivating expression of repressed target genes ( 37 , 154 , 155 ). BET inhibitors induce cell cycle arrest and partially reverse expression of the EWS::FLI1 gene signature ( 73 , 150 – 152 ).…”

Section: Therapeutic Implications Of Ews::fli1 “High” and “Low” Cell ...mentioning

confidence: 99%

The importance of fusion protein activity in Ewing sarcoma and the cell intrinsic and extrinsic factors that regulate it: A review

2022

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Accumulating evidence shows that despite clonal origins tumors eventually become complex communities comprised of phenotypically distinct cell subpopulations. This heterogeneity arises from both tumor cell intrinsic programs and signals from spatially and temporally dynamic microenvironments. While pediatric cancers usually lack the mutational burden of adult cancers, they still exhibit high levels of cellular heterogeneity that are largely mediated by epigenetic mechanisms. Ewing sarcomas are aggressive bone and soft tissue malignancies with peak incidence in adolescence and the prognosis for patients with relapsed and metastatic disease is dismal. Ewing sarcomas are driven by a single pathognomonic fusion between a FET protein and an ETS family transcription factor, the most common of which is EWS::FLI1. Despite sharing a single driver mutation, Ewing sarcoma cells demonstrate a high degree of transcriptional heterogeneity both between and within tumors. Recent studies have identified differential fusion protein activity as a key source of this heterogeneity which leads to profoundly different cellular phenotypes. Paradoxically, increased invasive and metastatic potential is associated with lower EWS::FLI1 activity. Here, we review what is currently understood about EWS::FLI1 activity, the cell autonomous and tumor microenvironmental factors that regulate it, and the downstream consequences of these activity states on tumor progression. We specifically highlight how transcription factor regulation, signaling pathway modulation, and the extracellular matrix intersect to create a complex network of tumor cell phenotypes. We propose that elucidation of the mechanisms by which these essential elements interact will enable the development of novel therapeutic approaches that are designed to target this complexity and ultimately improve patient outcomes.

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“…Interestingly, HDACi could be chemically modified to have a second pharmacophore, like fimepinostat, which is a hybrid inhibitor of phosphatidylinositol 3-kinase (PI3K) and HDACs. This drug not only reduced EWSR1-FLI1 protein by affecting its stability but also cell viability and tumor growth in sarcoma xenograft models [ 52 ].…”

Section: Epigenetic and Immunotherapy-based Treatments In Ews: Moving...mentioning

confidence: 99%

Ewing Sarcoma Meets Epigenetics, Immunology and Nanomedicine: Moving Forward into Novel Therapeutic Strategies

Sánchez-Molina

Figuerola-Bou

Sánchez-Margalet

et al. 2022

Cancers

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Ewing Sarcoma (EWS) is an aggressive bone and soft tissue tumor that mainly affects children, adolescents, and young adults. The standard therapy, including chemotherapy, surgery, and radiotherapy, has substantially improved the survival of EWS patients with localized disease. Unfortunately, this multimodal treatment remains elusive in clinics for those patients with recurrent or metastatic disease who have an unfavorable prognosis. Consistently, there is an urgent need to find new strategies for patients that fail to respond to standard therapies. In this regard, in the last decade, treatments targeting epigenetic dependencies in tumor cells and the immune system have emerged into the clinical scenario. Additionally, recent advances in nanomedicine provide novel delivery drug systems, which may address challenges such as side effects and toxicity. Therefore, therapeutic strategies stemming from epigenetics, immunology, and nanomedicine yield promising alternatives for treating these patients. In this review, we highlight the most relevant EWS preclinical and clinical studies in epigenetics, immunotherapy, and nanotherapy conducted in the last five years.

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RETRACTED: Inhibition of HDACs reduces Ewing sarcoma tumor growth through EWS-FLI1 protein destabilization

Cited by 3 publications

References 54 publications

Drug Targeting of Chromosomal Translocations in Fusion-Positive Sarcoma

Drug Targeting of Chromosomal Translocations in Fusion-Positive Sarcoma

The importance of fusion protein activity in Ewing sarcoma and the cell intrinsic and extrinsic factors that regulate it: A review

Ewing Sarcoma Meets Epigenetics, Immunology and Nanomedicine: Moving Forward into Novel Therapeutic Strategies

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