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  • In contrast irinotecan has shown

    2021-02-23

    In contrast, irinotecan has shown much less myelosuppression and may be more active in Ewing sarcoma both alone and in combination with temozolamide. One phase II study of 13 heavily pretreated Ewing sarcoma patients demonstrated a response rate of 38% including 2 complete responses (Bisogno et al., 2006). Irinotecan has also shown significant activity in combination with temozolamide. A single center retrospective review of 19 pretreated Ewing sarcoma patients demonstrated an overall response rate of 63% with 5 documented complete responses (Casey et al., 2009). The most common toxicity observed in pediatric patients is diarrhea likely related to metabolism of the drug by intestinal flora, an effect that can be at least partially mitigated by administration of oral cephalosporins (Furman et al., 1999, Wagner et al., 2008, McGregor et al., 2012). It is notable that there is significant schedule dependence to the activity of these compounds consistent with their activity in S-phase that mitigates the myelosuppression particularly for irinotecan (Houghton et al., 1995). Together these studies suggest that further prospective evaluation of camptothecins and in particular irinotecan as both a single agent and in combination therapies is warranted. This notion is further supported by recent preclinical work that suggests a particular sensitivity of Ewing sarcoma to these agents. In one study, gene expression data, chromosomal copy number and sequencing data were cross-referenced with novel pharmacological evaluations of 24 different agents in 479 human cancer cell lines. The Ewing sarcoma cell lines were among the most sensitive cell lines tested to camptothecin and showed the highest expression of SLFN11, a gene identified as a predictor of camptothecin sensitivity (Barretina et al., 2012). In addition, a recent drug screen to identify inhibitors of the EWS–FLI1 transcription factor (described below), identified among the active inhibitors of EWS–FLI1 camptothecin (Boro et al., 2012). It is notable that we independently identified camptothecins in our high throughput screen described below although we did not fully characterize this OSI-930 in lieu of other more effective inhibitors (unpublished data).
    ET-743 (Ecteinascidin 743, Trabectedin, Yondelis™) ET-743 is a natural product isolated from the sea squirt Ecteinascidia turbinate. The drug has been extensively studied in phase I and II studies in sarcomas in both the United States and Europe and found to have activity in leiomyosarcoma, liposarcoma, malignant fibrous histiocytoma, and synovial sarcoma (Chuk et al., 2009, Thornton, 2010). However, the most impressive response rates have occurred in myxoid liposarcoma where an almost 50% response rate has been observed in some series (Grosso et al., 2009, Cesne et al., 2012). Elegant preclinical work has demonstrated that this particular sensitivity of myxoid liposarcoma may be due to the drug's ability to block the activity of the FUS-CHOP oncogene, allowing the tumor to differentiate into benign lipoblasts (Forni et al., 2009, Frapolli et al., 2010). This theory was further supported by work that showed that in an animal model of FUS-CHOP tumorigenesis, the drug is able to release the FUS-CHOP mediated block in differentiation again allowing the tumor to become benign lipoblasts (Charytonowicz et al., 2012). Given the broad range of responses in sarcoma and activity against ML in particular, it seemed as though the drug may have particular activity against translocation positive sarcomas, a theory being tested in a randomized phase III trial. Since Ewing sarcoma is a translocation positive sarcoma OSI-930 and FUS and EWS are family members, it follows that Ewing sarcoma might also display a particular sensitivity to the drug. The evaluation of ET-743 in children initially lent credence to this theory. In a phase I study of 13 patients, 2 out of 3 Ewing sarcoma patients treated with the drug responded, one patient with widely metastatic disease had a complete response (Lau et al., 2005). In another case series of Ewing sarcoma patients, a 25% progression free survival rate was observed (Dileo et al., 2007). In addition, preclinical reports have shown that Ewing sarcoma cells are among the most sensitive to the drug in vitro with sub-nanomolar IC50s (Scotlandi et al., 2002, Aune et al., 2008). Furthermore, we have shown that the drug interferes with the activity of EWS–FLI1 at the promoter and mRNA level and effectively reverses a gene signature of EWS–FLI1 in vitro (Grohar, Griffin et al., 2011). Unfortunately, a recent phase II did not support the activity of this agent in Ewing sarcoma as 1 out of 11 patients with Ewing sarcoma who received ET-743 had stable disease and the rest progressed on therapy. A recent phase I trial at the National Cancer Institute also did not show activity in Ewing sarcoma, although only one patient with ES was enrolled in this study (Chuk et al., 2012).