Trial document




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  DRKS00011791

Trial Description

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Title

Evaluation of circulating miRNA profiles from patients with Ewing's sarcoma

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Trial Acronym

EcmiREs

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URL of the Trial

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Brief Summary in Lay Language

Almost every cell in our body carries genetic information in the form of DNA in its cell nucleus, which stores the information units (genes) for the production of innumerable proteins in our body. In order to ensure a coordinated production of proteins, cells have developed complex mechanisms for gene regulation. One of these mechanisms uses so-called microRNAs (miRNAs) - short sequences of genetic information that influence the expression of genes.
In recent years it has been shown that miRNA circulates in the blood and changes in concentration in various cancers. The aim of this study is the detection of miRNA in the blood during treatment. By combining the results of the blood analysis and the clinical information, we hope to characterize significantly altered miRNAs.

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Brief Summary in Scientific Language

Sarcomas compromise a heterogeneous group of malignant soft tissue tumors of mesenchymal origin that make up approximately 1% of all malignant tumors in adulthood and 15% of tumors in childhood and require a multidisciplinary approach including surgical resection of the tissue mass, radiotherapy for local disease control and systemic chemotherapy. More than a hundred histological sarcoma subtypes are classified by the world health organization (WHO) (Fletcher et al., IARC Press 2013), several of which have distinct molecular biological characteristics aiding classification.
In 85%-90% of cases, Ewing sarcomas are characterized by the t(11;22)(q24;q12) translocation resulting in fusion of the 5’ portion EWSR1 gene with the 3’ end of the FLI1 gene and generation of a chimeric EWS-FLI gene product which leads to an aberrant expression downstream targets such as the CD99 membrane receptor [1] that influences oncogenesis by alteration of growth and differentiation of tumor cells. Other translocation events lead to the expression of FUS-ERG or FUS-FEV, which are believed to function similarly to EWS based fusions due to the high similarity of FUS and EWS proteins.
Association of EWS as a component of the DROSHA complex [2] (described below) suggests involvement of the EWS-FLI fusion protein in microRNA (miRNA) biogenesis and knockdown of EWS in U2OS cell lines has been shown to lead to an increase of pre-let7g [3].
MicroRNAs are short, non-coding RNA molecules that are initially transcribed from inter-genic and intra-genic regions giving rise to pri-miRNAs in the nucleus. The pri-miRNA ribonucleoprotein then associates with DGCR8 and is then cleaved by the ribonuclease DROSHA leading to the formation of pre-miRNA of about 70nt in length, which is then exported from the nucleus and submitted to the next cleaving step mediated by the Dicer ribonuclease leading to the formation of 18-25nt long dsRNA, which then associates Argonaut 2 protein forming the RNA-induced silencing complex (RISC). Binding to the 3’UTR region of mRNA it then regulates protein expression by mRNA degradation or repression of translation. MiRNAs found in body fluids such as blood are remarkably stable [4], found in microvesicles [5] and probably take part in gene exchange [6] - specifically by exosomes in cancer, where they play an important role by activating monocytes [7].
Several groups have shown a striking impact of miRNAs in the pathogenesis of Ewing sarcoma, such as the presence of a mutually repressive feedback loop involving EWS-FLI1and miRNA-145 that represses SOX2 and OCT4 and thereby leads to lineage-restricted differentiation and inhibition of human embryonic stem cell pluripotency, as well as self-renewal [8] and the modulation of EYA3 expression, a DNA repair protein and transcriptional co-factor, through miRNA-708 repression by EWS-FLI1resulting in increased cell survival and chemoresistance [9]. Another finding includes the modulation of CD99 expression by miR-30a-5p [10].


1. Riggi, N. and I. Stamenkovic, The Biology of Ewing sarcoma. Cancer Lett, 2007. 254(1): p. 1-10.
2. Gregory, R.I., et al., The Microprocessor complex mediates the genesis of microRNAs. Nature, 2004. 432(7014): p. 235-40.
3. Sohn, E.J., et al., Accumulation of pre-let-7g and downregulation of mature let-7g with the depletion of EWS. Biochem Biophys Res Commun, 2012. 426(1): p. 89-93.
4. Mitchell, P.S., et al., Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A, 2008. 105(30): p. 10513-8.
5. Hunter, M.P., et al., Detection of microRNA expression in human peripheral blood microvesicles. PLoS One, 2008. 3(11): p. e3694.
6. Valadi, H., et al., Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol, 2007. 9(6): p. 654-9.
7. Baj-Krzyworzeka, M., et al., Tumour-derived microvesicles modulate biological activity of human monocytes. Immunol Lett, 2007. 113(2): p. 76-82.
8. Riggi, N., et al., EWS-FLI-1 modulates miRNA145 and SOX2 expression to initiate mesenchymal stem cell reprogramming toward Ewing sarcoma cancer stem cells. Genes Dev, 2010. 24(9): p. 916-32.
9. Robin, T.P., et al., EWS/FLI1 regulates EYA3 in Ewing sarcoma via modulation of miRNA-708, resulting in increased cell survival and chemoresistance. Mol Cancer Res, 2012. 10(8): p. 1098-108.
10. Franzetti, G.A., et al., MiR-30a-5p connects EWS-FLI1 and CD99, two major therapeutic targets in Ewing tumor. Oncogene, 2013. 32(33): p. 3915-21.

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Organizational Data

  •   DRKS00011791
  •   2017/08/18
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  •   yes
  •   Approved
  •   S-672/2016, Ethik-Kommission I der Medizinischen Fakultät Heidelberg
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Secondary IDs

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Health Condition or Problem studied

  •   C40 -  Malignant neoplasm of bone and articular cartilage of limbs
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Interventions/Observational Groups

  •   Isolation of circulating miRNA
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Characteristics

  •   Non-interventional
  •   Other
  •   Single arm study
  •   Open (masking not used)
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  •   Uncontrolled/Single arm
  •   Basic research/physiological study
  •   Single (group)
  •   N/A
  •   N/A
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Primary Outcome

The aim of the study is the characterization of circulating miRNA profiles in patients with Ewing's or Ewing-like sarcoma undergoing therapy.

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Secondary Outcome

/

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • University Medical Center 
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Recruitment

  •   Planned
  •   2017/10/01
  •   20
  •   Monocenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   no maximum age
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Additional Inclusion Criteria

Patients with secured Ewing's or Ewing-like sarcoma that have the ability to consent

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Exclusion Criteria

Lack of ability to consent

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Addresses

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    • Universitätsklinikum Heidelberg, Medizinische Klinik V
    • Mr.  MUDr.   Philipp   Novotny 
    • Im Neuenheimer Feld 410
    • 69120  Heidelberg
    • Germany
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    • Universitätsklinikum HeidelbergMedizinische Klinik V
    • Mr.  MUDr.  Philipp  Novotny 
    • Im Neuenheimer Feld 410
    • 69120  Heidelberg
    • Germany
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    • Universitätsklinikum HeidelbergMedizinische Klinik V
    • Mr.  MUDr.   Philipp  Novotny 
    • Im Neuenheimer Feld 410
    • 69120  Heidelberg
    • Germany
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Sources of Monetary or Material Support

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    • Monika Kutzner Stiftung Rechtsfähige Stiftung des privaten Rechts zur Förderung der Krebsforschung
    • Bayerische Str. 8
    • 10707  Berlin
    • Germany
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Status

  •   Recruiting planned
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Trial Publications, Results and other Documents

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