bims-myxlip Biomed News
on Myxoid liposarcoma
Issue of 2022‒06‒05
two papers selected by
Laura Mannarino
Humanitas Research

  1. Asian Pac J Cancer Prev. 2022 May 01. pii: 90102. [Epub ahead of print]23(5): 1539-1545
      OBJECTIVE: Among sarcomas, Ewing sarcoma (EWS) is characterized as a highly malignant type of bone tumor caused by the fusion of EWS RNA Binding Protein-1 (EWSR1)/ Friend leukemia integration 1 (FLI1) genes. The product of fusion gene gives rise to EWSR1/FLI1 which activates the activity of Eyes absent homolog 3 (EYA3) which causes tumor growth and angiogenesis. EYA3 is now considered as a therapeutic drug target for EWS . The study was designed to gather potential inhibitors for the EYA3 target using medicinal compounds.METHODS: In this study, we have obtained a list of medicinal compounds from the NuBBE database and downloaded their structural information. Then insilico screening analysis of >2,000 medicinal compounds was performed with PyRX virtual drug screening software to discover potential inhibitors for the treatment of EWS.
    RESULTS: Our investigation revealed that Sorbifolin and 1,7-Dihydroxy-3-methylanthracene-9.10-dione show interactive affinity for EYA3 active residues. Moreover, these compounds have adequate toxicity, can induce cytotoxicity in EWS cells, and are capable of regulating the expression of genes activated by EWSR1/FLI1.
    CONCLUSION: Our study concluded that Sorbifolin and 1,7-Dihydroxy-3-methylanthracene-9.10-dione are promising drug candidates for the treatment of EWS and should be further subjected to invitro testing.
    Keywords:  Ewing sarcoma; Eyes Absent Homolog-3; In silico Gene expression; Medicinal Compounds; Virtual screening
  2. Mol Cancer Ther. 2022 Jun 02. pii: molcanther.1003.2021. [Epub ahead of print]
      DSRCT is a rare pediatric sarcoma with a poor overall survival. This tumor is absolutely dependent on the continued expression and activity of its defining molecular lesion, the EWS-WT1 transcription factor. Unfortunately, the therapeutic targeting of transcription factors is challenging and there is a critical need to identify compounds that inhibit EWS-WT1. Here we show that the compound lurbinectedin inhibits EWS-WT1 by redistributing the protein within the nucleus to the nucleolus. This nucleolar redistribution interferes with the activity of EWS-WT1 to reverse expression over 70% of the transcriptome. In addition, the compound blocks expression of the EWS-WT1 fusion protein to inhibit cell proliferation at the lowest GI50 ever reported for this compound in any cell type. The effects occur at concentrations that are easily achievable in the clinic and translate to the in vivo setting to cause tumor regressions in multiple mice in a xenograft and PDX model of DSRCT. Importantly, this mechanism of nucleolar redistribution is also seen with wild-type EWSR1 and the related fusion protein EWS-FLI1. This provides evidence for a "class effect" for the more than 18 tumors driven by EWSR1 fusion proteins. More importantly, the data establishes lurbinectedin as a promising clinical candidate for DSRCT.