Small molecule selected to disrupt oncogenic protein EWS-FLI1 interaction with RNA Helicase A inhibits Ewing's Sarcoma

Georgetown University, Lombardi Comprehensive Cancer Center, Department of Oncology, Washington, DC, USA.
Nature medicine (Impact Factor: 27.36). 08/2009; 15(7):750-6. DOI: 10.1038/nm.1983
Source: PubMed


Many sarcomas and leukemias carry nonrandom chromosomal translocations encoding tumor-specific mutant fusion transcription factors that are essential to their molecular pathogenesis. Ewing's sarcoma family tumors (ESFTs) contain a characteristic t(11;22) translocation leading to expression of the oncogenic fusion protein EWS-FLI1. EWS-FLI1 is a disordered protein that precludes standard structure-based small-molecule inhibitor design. EWS-FLI1 binding to RNA helicase A (RHA) is important for its oncogenic function. We therefore used surface plasmon resonance screening to identify compounds that bind EWS-FLI1 and might block its interaction with RHA. YK-4-279, a derivative of the lead compound from the screen, blocks RHA binding to EWS-FLI1, induces apoptosis in ESFT cells and reduces the growth of ESFT orthotopic xenografts. These findings provide proof of principle that inhibiting the interaction of mutant cancer-specific transcription factors with the normal cellular binding partners required for their oncogenic activity provides a promising strategy for the development of uniquely effective, tumor-specific anticancer agents.

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Available from: Hayriye Verda Erkizan, Jan 11, 2014
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    • "Survival of patients with localised disease has improved substantially by modern multimodal treatment regimens (Paulussen et al, 1998), but primary multifocal disease or disseminated relapse often remains incurable (Ladenstein et al, 2010). Novel treatment strategies aim to eliminate residual microscopic disease remaining after standard therapy and include molecularly targeted drugs and antibodies (Erkizan et al, 2009; Juergens et al, 2011) as well as immunological therapies (Mackall et al, 2008; Kailayangiri et al, 2012). One approach is based on the genetic engineering of T cells with recombinant chimeric antigen receptors (CARs) directed against the ganglioside antigen G D2 that is overexpressed on many Ewing sarcomas (Kailayangiri et al, 2012). "
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    ABSTRACT: Background: Novel treatment strategies in Ewing sarcoma include targeted cellular therapies. Preclinical in vivo models are needed that reflect their activity against systemic (micro)metastatic disease. Methods: Whole-body magnetic resonance imaging (WB-MRI) was used to monitor the engraftment and dissemination of human Ewing sarcoma xenografts in mice. In this model, we evaluated the therapeutic efficacy of T cells redirected against the Ewing sarcoma-associated antigen GD2 by chimeric receptor engineering. Results: Of 18 mice receiving intravenous injections of VH-64 Ewing sarcoma cells, all developed disseminated tumour growth detectable by WB-MRI. All mice had lung tumours, and the majority had additional manifestations in the bone, soft tissues, and/or kidney. Sequential scans revealed in vivo growth of tumours. Diffusion-weighted whole-body imaging with background signal suppression effectively visualised Ewing sarcoma growth in extrapulmonary sites. Animals receiving GD2-targeted T-cell therapy had lower numbers of pulmonary tumours than controls, and the median volume of soft tissue tumours at first detection was lower, with a tumour growth delay over time. Conclusion: Magnetic resonance imaging reliably visualises disseminated Ewing sarcoma growth in mice. GD2-retargeted T cells can noticeably delay tumour growth and reduce pulmonary Ewing sarcoma manifestations in this aggressive disease model.
    Full-text · Article · Jul 2013 · British Journal of Cancer
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    • "This link is fundamental for its oncogenic function in Ewing sarcoma. A specific small molecule, YK-4_279, can block RHA binding to EWS/FLI1, inducing apoptosis in Ewing sarcoma cells and reducing the growth of tumor cell in mice [116]. It was also described a novel peptide, defined ESAP1, able to bind EWS/FLI1 chimeric protein, with high affinity, altering cell-cycle process in Ewing sarcoma cells [117]. "
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    ABSTRACT: Soft tissue tumors are a heterogeneous group of tumors, traditionally classified according to morphology and histogenesis. Molecular classification divides sarcomas into two main categories: (a) sarcomas with specific genetic alterations and (b) sarcomas showing multiple complex karyotypic abnormalities without any specific pattern. Most chromosomal alterations are represented by translocations which are increasingly detected. The identification of fusion transcripts, in fact, not only support the diagnosis but also provides the basis for the development of new therapeutic strategies aimed at blocking aberrant activity of the chimeric proteins. One of the genes most susceptible to breakage/translocation in soft tissue tumors is represented by Ewing sarcoma breakpoint region 1 (EWSR1). This gene has a large number of fusion partners, mainly associated with the pathogenesis of Ewing's sarcoma but with other soft tissue tumors too. In this review, we illustrate the characteristics of this gene/protein, both in normal cellular physiology and in carcinogenesis. We describe the different fusion partners of EWSR1, the molecular pathways in which is involved and the main molecular biology techniques for the identification of fusion transcripts and for their inhibition.
    Full-text · Article · Mar 2013 · Medical Oncology
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    • "Such genetic abnormalities were considered in diagnosis and prognosis [8], and typical mutations in the tyrosine kinase KIT were targeted in GIST [9] [10]. Recently, the proteins binding to the chimeric gene product were also reported as a therapeutic target in Ewing sarcoma [11]. However, typical molecular backgrounds of unique genetic alterations have not been reported for most sarcomas. "
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    ABSTRACT: Sarcomas range from curable tumors to those causing death via metastasis and recurrence. Thus, there is an urgent need for biomarker identification in order to assess the degree of malignancy, predict prognosis, and evaluate possible therapies. Various proteomic approaches and different clinical materials have been used to this end, and candidate biomarkers have been reported for the different types of sarcomas. However, the sample size used in these biomarker studies was generally insufficient, and thus far, no biomarker has been proved useful in clinics. Given that sarcomas are rare, biomarker validation in this setting is more challenging than in other malignancies. In gastrointestinal stromal tumor, adjuvant therapy has proven to be effective. However, only 40% patients experience metastasis after curative surgery alone, and the rest of the patients may not need adjuvant therapy. Using a proteomic approach, we identified pfetin (potassium channel tetramerisation domain containing 12, KCTD 12) as a novel prognostic biomarker for sarcoma, and immunohistochemically confirmed its clinical usefulness by a multi-institutional validation study. Here, we describe our experience and discuss the critical points in the discovery of this biomarker.
    Full-text · Article · Jan 2013 · PROTEOMICS - CLINICAL APPLICATIONS
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