Ewing sarcoma: investigational mono- and combination therapies in clinical trials

Gartrell, Jessica; Rodríguez‐Galindo, Carlos

doi:10.1080/13543784.2021.1919623

Cited by 7 publications

(6 citation statements)

References 74 publications

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“…Ewing sarcoma ranks second in the incidence of primary malignant bone tumors among children and adolescents, and its proportion in primary bone tumors is 6% to 8% [1]. After traditional surgery, radiotherapy and chemotherapy, most patients will die within 2 years, and the five-year survival rate is under 10% [2,3]. After IGF-1R is activated and overexpressed in Ewing sarcoma, it may have a synergistic effect on the fusion gene EWS-FLI1, thus driving the occurrence of Ewing sarcoma [4,6].…”

Section: Discussionmentioning

confidence: 99%

“…The disease is characterized by a short disease course, rapid metastasis, and high malignancy. The current primary treatments for Ewing sarcoma are surgery alone, radiotherapy, and single-agent chemotherapy [2]. However, none of the treatments have favorable outcomes, and most patients will die within 2 years, with 5-year survival rates of no more than 10% [3].…”

Section: Introductionmentioning

confidence: 99%

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Effective natural inhibitors targeting IGF-1R by computational study

Wang

Zhou

Lin

et al. 2022

Aging

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IGF-1R belongs to a tyrosine kinase family and is currently a newly discovered drug target. IGF-1R inhibitors can bind directly to IGF-1R to achieve the effect of inhibiting the function of IGF-1R. At present, IGF-1R inhibitors have good clinical effects on Ewing sarcoma in the clinic. In this article, we screened compounds capable of inhibiting IGF-1R function through computer-aided virtual technology. First, some molecules with good docking properties for IGF-1R can be screened by LibDock. Then, ADME analysis (adsorption, distribution, metabolism, and excretion) and toxicity indicators were performed. The mechanism of binding and the binding affinity in the middle of IGF-1R and ligand were verified using molecular docking. Ultimately, the stability of ligand-receptor complex was evaluated using molecular dynamics simulations. In line with the results, two natural compounds ZINC000014946303 and ZINC000006003042 were found in the ZINC database, potential effective inhibitors of IGF-1R. ZINC000014946303 and ZINC000006003042 can bind to IGF-1R with high binding affinity as predicted by molecular docking. It was also found that they are not hepatotoxic, with less developmental toxicity potential, rodent carcinogenicity, Ames mutagenicity, and high tolerance to cytochrome P4502D6. Hereby, this study aimed to screen out ideal compounds that have inhibitory effects on IGF-1R from the drug library and, at the same time, provide a direction for the future development of IGF-1R inhibitors.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effective natural inhibitors targeting IGF-1R by computational study

Wang

Zhou

Lin

et al. 2022

Aging

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“…It has the second-highest incidence of all primary bone tumors, accounting for 6 to 8 percent [2]. Ewing sarcoma metastasizes quickly and has a high degree of malignancy [3]. Traditional therapy methods for Ewing sarcoma, such as surgery, radiotherapy, and chemotherapy, are hard to reach notably satisfactory results [4].…”

Section: Introductionmentioning

confidence: 99%

Effective natural inhibitors targeting LSD1 by computational study

Wang

Lin

Zhou

et al. 2023

Preprint

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Objective: This study aimed to screen lead compounds and drug candidates with an inhibitory effect on the function of LSD1 from the ZINC database. Methods: We used computer-aided virtual technology to screen some agents that inhibit the function of LSD1. Initially, LibDock screened out some optimal compounds for docking with LSD1. These candidate compounds were subjected to ADME analysis (adsorption, distribution, metabolism, and excretion) and toxicity metrics. Molecular docking can determine the binding affinity between LSD1 and the ligand, and lastly, we applied molecular dynamics simulations to calculate the docking of the ligand-receptor complex. Results: Two natural compounds, ZINC000001651126 and ZINC000000001083, found in the ZINC database, are potent inhibitors of LSD1. When ZINC000001651126 and ZINC000000001083 bind to LSD1, they show high binding affinity. They are not hepatotoxic and have a high tolerance to cytochrome P4502D6. In addition, ZINC000001651126 and ZINC000000001083 have less developmental toxicity potential, rodent carcinogenicity, and Ames mutagenicity. Conclusions: ZINC000001651126 and ZINC000000001083 can be considered safe and ideal drug candidates for LSD1 inhibitors. This study can provide new ideas for future research and the application of LSD1 inhibitors.

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“…EWS-FLI1 can function as a pioneer transcription factor by binding to genomic elements enriched in polymorphic GGAA microsatellites, inducing chromatin reorganization and formation of de novo enhancers and superenhancers ( 4, 5 ). Numerous groups have attempted to target this chimera or critical downstream effectors therapeutically; however, none have been clinically successful, underscoring the need for alternate strategies ( 6 ).…”

Section: Introductionmentioning

confidence: 99%

Natural Killer Cell Activation by Ubiquitin-specific Protease 6 Mediates Tumor Suppression in Ewing Sarcoma

Jain

Henrich

Quick

et al. 2023

Cancer Research Communications

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Ewing sarcoma (ES) is a rare and deadly pediatric bone cancer for which survival rates and treatment options have stagnated for decades. ES has not benefited from immunotherapy due to poor understanding of how its immune landscape is regulated. We recently reported that Ubiquitin-Specific Protease 6 (USP6) functions as a tumor suppressor in ES, and identified it as the first cell-intrinsic factor to modulate the ES immune tumor microenvironment (TME). USP6 induces intratumoral infiltration and activation of multiple innate immune lineages in xenografted nude mice. Here we report that natural killer (NK) cells are essential for its tumor-inhibitory functions, as NK cell depletion reverses USP6-mediated suppression of ES xenograft growth. USP6 expression in ES cells directly stimulates NK cell activation and degranulation in vitro, and functions by increasing surface levels of multiple NK-activating ligands. USP6 also induces surface upregulation of the receptor for the apoptosis-inducing ligand TRAIL, providing an additional route for enhanced sensitivity to NK killing. Furthermore, USP6-expressing ES and NK cells participate in a paracrine immunostimulatory feedforward loop, wherein interferon-gamma secreted by activated NK cells feeds back on USP6/ES cells to induce synergistic expression of chemokines CXCL9 and CXCL10. Remarkably, expression of USP6 in subcutaneous ES xenografts induces systemic activation and maturation of NK cells, and induces an abscopal response in which growth of distal tumors is inhibited, coincident with increased infiltration and activation of NK cells. This work reveals how USP6 reprograms the ES TME to enhance anti-tumor immunity, and may be exploited for future therapeutic benefit.

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Ewing sarcoma: investigational mono- and combination therapies in clinical trials

Cited by 7 publications

References 74 publications

Effective natural inhibitors targeting IGF-1R by computational study

Effective natural inhibitors targeting IGF-1R by computational study

Effective natural inhibitors targeting LSD1 by computational study

Natural Killer Cell Activation by Ubiquitin-specific Protease 6 Mediates Tumor Suppression in Ewing Sarcoma

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