Novel peptide binds EWS-FLI1 and reduces the oncogenic potential in Ewing tumors

Erkizan, Hayriye V.; Scher, Lauren; Gamble, S. Ellen; Barber‐Rotenberg, Julie S.; Sajwan, Kamal; Üren, Aykut; Toretsky, Jeffrey A.

doi:10.4161/cc.10.19.17734

Cited by 28 publications

(19 citation statements)

References 38 publications

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“…Several small molecule inhibitors of EWS/Fli1 have been identified. Interestingly, they all have aromatic character [78]–[80] or, in one case, a very basic short peptide sequence [81]. Whether any of them target the EAD portion of EWS/Fli is unknown.…”

Section: Discussionmentioning

confidence: 99%

Polycation-π Interactions Are a Driving Force for Molecular Recognition by an Intrinsically Disordered Oncoprotein Family

Song

Tompa

et al. 2013

PLoS Comput Biol

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Molecular recognition by intrinsically disordered proteins (IDPs) commonly involves specific localized contacts and target-induced disorder to order transitions. However, some IDPs remain disordered in the bound state, a phenomenon coined “fuzziness”, often characterized by IDP polyvalency, sequence-insensitivity and a dynamic ensemble of disordered bound-state conformations. Besides the above general features, specific biophysical models for fuzzy interactions are mostly lacking. The transcriptional activation domain of the Ewing's Sarcoma oncoprotein family (EAD) is an IDP that exhibits many features of fuzziness, with multiple EAD aromatic side chains driving molecular recognition. Considering the prevalent role of cation-π interactions at various protein-protein interfaces, we hypothesized that EAD-target binding involves polycation- π contacts between a disordered EAD and basic residues on the target. Herein we evaluated the polycation-π hypothesis via functional and theoretical interrogation of EAD variants. The experimental effects of a range of EAD sequence variations, including aromatic number, aromatic density and charge perturbations, all support the cation-π model. Moreover, the activity trends observed are well captured by a coarse-grained EAD chain model and a corresponding analytical model based on interaction between EAD aromatics and surface cations of a generic globular target. EAD-target binding, in the context of pathological Ewing's Sarcoma oncoproteins, is thus seen to be driven by a balance between EAD conformational entropy and favorable EAD-target cation-π contacts. Such a highly versatile mode of molecular recognition offers a general conceptual framework for promiscuous target recognition by polyvalent IDPs.

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Section: Discussionmentioning

confidence: 99%

Polycation-π Interactions Are a Driving Force for Molecular Recognition by an Intrinsically Disordered Oncoprotein Family

Song

Tompa

et al. 2013

PLoS Comput Biol

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“…The complete lack of EWS-FLI-1 expression in healthy cells, coupled with the absolute requirement of diseased cells to maintain expression of this gene (27, 28), have led to the development of several EWS-FLI-1-targeting therapies in recent years. While many of these studies have concentrated on disrupting the function of this oncogene (29, 30), studies are also being conducted which attempt to activate the immune system specifically to target cells carrying EWS-FLI-1.…”

Section: Discussionmentioning

confidence: 99%

EWS-FLI-1-Targeted Cytotoxic T-cell Killing of Multiple Tumor Types Belonging to the Ewing Sarcoma Family of Tumors

Evans

Liu

Porter

et al. 2012

Clinical Cancer Research

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Purpose The Ewing Sarcoma Family of Tumors (ESFTs) comprises a group of aggressive, malignant bone and soft tissue tumors that predominantly affect children and young adults. These tumors frequently share expression of the EWS-FLI-1 translocation, which is central to tumor survival but not present in healthy cells. In this study, we examined EWS-FLI-1 antigens for their capacity to induce immunity against a range of ESFT types. Design Computer prediction analysis of peptide binding, HLA-A2.1 stabilization assays, and induction of Cytotoxic T-Lymphocytes (CTL) in immunized HLA-A2.1 transgenic mice were used to assess the immunogenicity of native and modified peptides derived from the fusion region of EWS-FLI-1 type 1. CTL-killing of multiple ESFT family members in vitro, and control of established xenografts in vivo, was assessed. We also examined whether these peptides could induce human CTLs in vitro. Results EWS-FLI-1 type 1 peptides were unable to stabilize cell surface HLA-A2.1 and induced weak CTL activity against Ewing Sarcoma cells. In contrast, peptides with modified anchor residues induced potent CTL killing of Ewing Sarcoma cells presenting endogenous (native) peptides. The adoptive transfer of CTL specific for the modified peptide YLNPSVDSV resulted in enhanced survival of mice with established Ewing Sarcoma xenografts. YLNPSVDSV-specific CTL displayed potent killing of multiple ESFT types in vitro: Ewing Sarcoma, pPNET, Askin’s Tumor, and Biphenotypic Sarcoma. Stimulation of human Peripheral Blood Mononuclear Cells with YLNPSVDSV peptide resulted in potent CTL-killing. Conclusions These data show that YLNPSVDSV peptide is a promising antigen for ESFT immunotherapy and warrants further clinical development.

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“…Erkizan et al (2011) identified a potential scaffold for Ewing’s sarcoma, through the isolation of 27 binding peptides; the author found that the peptide ESAP1 shows a high binding to EWS-FLI1 in bone cancer. The minimal interaction region of ESAP1 was characterized and the lysine residues were found to be critical for cellular cytotoxicity.…”

Section: Ewing Sarcomamentioning

confidence: 99%

“…The minimal interaction region of ESAP1 was characterized and the lysine residues were found to be critical for cellular cytotoxicity. ESAP1 reduces the transcriptional activity of EWS-FLI1 and also disrupts cell cycle kinetics in Ewing tumor cells (Erkizan et al, 2011) ( Figure 2 ).…”

Section: Ewing Sarcomamentioning

confidence: 99%

Biomarkers of Osteosarcoma, Chondrosarcoma, and Ewing Sarcoma

et al. 2017

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Osteosarcoma is the most frequent malignant bone neoplasm, followed by chondrosarcoma and Ewing sarcoma. The diagnosis of bone neoplasms is generally made through histological evaluation of a biopsy. Clinical and radiological features are also important in aiding diagnosis and to complete the staging of bone cancer. In addition to these, there are several non-specific serological or specific molecular markers for bone neoplasms. In bone tumors, molecular markers increase the accuracy of the diagnosis and assist in subtyping bone tumors. Here, we review these markers and discuss their role in the diagnosis and prognosis of the three most frequent malignant bone neoplasms, namely osteosarcoma, chondrosarcoma, and Ewing sarcoma.

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Novel peptide binds EWS-FLI1 and reduces the oncogenic potential in Ewing tumors

Cited by 28 publications

References 38 publications

Polycation-π Interactions Are a Driving Force for Molecular Recognition by an Intrinsically Disordered Oncoprotein Family

Polycation-π Interactions Are a Driving Force for Molecular Recognition by an Intrinsically Disordered Oncoprotein Family

EWS-FLI-1-Targeted Cytotoxic T-cell Killing of Multiple Tumor Types Belonging to the Ewing Sarcoma Family of Tumors

Biomarkers of Osteosarcoma, Chondrosarcoma, and Ewing Sarcoma

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