• 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • Other studies have investigated the role of HDAC


    Other studies have investigated the role of HDAC inhibitors in particular signaling pathways mediated by EWS–FLI1 (Matsumoto et al., 2001). A recent investigation, showed a physical association of EWS–FLI1 and HDAC1 that helps mediate a disruption in the p53 activation of downstream targets (Li et al., 2012). Disruption of HDAC1 with the HDAC inhibitor trichostatin A (TSA) restored the competency of this pathway, potentially providing the basis for combination therapies involving cytotoxic agents and TSA. Other epigenetic complexes have also been linked to important features in the biology of Ewing sarcoma. For example, EWS–FLI1 has been shown to directly regulate the polycomb complex gene EZH2 to help maintain a block in the differentiation of the tumors and facilitate metastatic spread (Richter et al., 2009). These results mirrored an earlier finding that showed that expression of EWS–FLI1 in mesenchymal stem Thonzonium Bromide sale upregulates EZH2 and triggers a transcriptional program that is similar to Ewing tumors (Riggi et al., 2008). Similarly, the expression of EWS–FLI1 in neural crest cells leads to the induction of EZH2 and another polycomb gene, BMI1 potentially creating a program permissive for EWS–FLI1 mediated transformation (von Levetzow et al., 2011). In the clinic, the HDAC inhibitor vorinostat has been evaluated in children in the relapsed refractory setting. Unfortunately, single agent activity in Ewing sarcoma has not been observed, although only 2 patients with Ewing sarcoma received the drug (Fouladi et al., 2010). However, abnormal chromatin structure in Ewing sarcoma cells is a component of both the genotype and phenotype of this tumor. EWS–FLI1 drives the expression of genes that in turn suppress a large percentage of the genome by modifying the availability of chromatin to the transcriptional machinery. These genes allow Ewing sarcoma cells to evade senescence and apoptosis in the setting of genetic damage and help the cells maintain a more de-differentiated state. It follows that ES cells are in turn sensitive to these agents both alone and in combination with other agents in preclinical models. Therefore, further investigation of these agents in Ewing sarcoma in a prospective fashion is warranted. In addition, work continues to develop more specific small molecules and combination therapies that recapitulate the preclinical success of these agents in the clinic.
    Targeting the EWS–FLI1 transcription factor The defining molecular feature of Ewing sarcoma is the characteristic EWSR1 and ETS fusion protein (Delattre et al., 1992). The most common fusion transcription involves EWSR1 and FLI1 and is derived from the t(11;22)(q24;q12) chromosomal translocation (Delattre et al., 1992, May et al., 1993). The biology of this tumor revolves around this molecular feature (Riggi & Stamenkovic, 2007). Experiments that silence EWS–FLI1 have shown clearly that the translocation influences the expression of over 500 to 1000 genes (Kauer et al., 2009). The resulting genetic program is believed to mitigate all aspects of oncogenesis and progression (Riggi & Stamenkovic, 2007). In addition, silencing of EWS–FLI1 using antisense DNA, siRNA and dominant negatives markedly impairs Ewing sarcoma cell growth (Maksimenko & Malvy, 2005). Unfortunately, the fusion protein is a transcription factor and therefore a challenging drug target. However, given the importance of the target, a number of strategies have been employed to try to identify small molecule inhibitors of EWS–FLI1. The first report of an EWS–FLI1 inhibitor employed functional drug screening and a novel gene signature approach that utilized branched chain technology to screen a library of clinically relevant small molecules to identify inhibitors of EWS–FLI1 (Stegmaier et al., 2007). The lead compound identified from this study was cytarabine, which depressed EWS–FLI1 protein expression, interfered with anchorage independent growth and impaired A673 xenograft growth (Stegmaier et al., 2007). Furthermore, older literature supported the in vitro sensitivity of Ewing sarcoma cells to cytarabine with IC50s that paralleled that of leukemia cell lines (Hofbauer et al., 1993). Unfortunately, the clinical translation of this compound was not successful. The phase II study evaluated 10 patients and found only one patient to have stable disease (DuBois et al., 2009). The limitations of the clinical study may explain this outcome and provide insight into future trials. First, although the screen was for a defined target, EWS–FLI1, only 5 of 10 patients treated had this documented translocation. Second, although historical pharmacokinetic data indicates that concentrations of cytarabine sufficient to inhibit EWS–FLI1 were achieved, it is not known if 5days of these concentrations in a 21-day cycle are enough to impair tumor growth or if the metabolism of this drug in patients allows active concentrations of drug to be achieved in Ewing sarcoma cells. Finally, there is no good pharmacodynamic marker of EWS–FLI1 activity and so it is not known if downstream target expression was suppressed in the tumors.