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  • Nevertheless because of the preclinical work


    Nevertheless, because of the preclinical work and the interference with EWS–FLI1 transcriptional activity, we believe that there may be a role for ET-743 in Ewing sarcoma. An analysis of the pharmacokinetic data published in the phase II clinical trial shows that at most the drug spent 5 to 6days out of 21 above the IC50 of Ewing sarcoma apr 246 sale with wide confidence intervals. In addition, our preclinical data has shown strong suppression of EWS–FLI1 at concentrations above 1nM, serum levels that would only have been achieved for 48h in the patient in this report (Lau et al., 2005). In addition, recent work has demonstrated limited sensitivity of xenograft models as a single agent on a similar schedule (manuscript in preparation). Nevertheless, in the COG phase I trial, a patient with widely metastatic Ewing sarcoma achieved a complete response. Therefore, more work needs to be done in the clinical and preclinical arena to study the dose and schedule of the drug in Ewing sarcoma. In addition, it is likely that the role of this drug in Ewing sarcoma will be in the setting of combination therapies (Scotlandi et al., 2002). Alternatively, new analogs of ET-743 such as Zalipsys™ and PM001183 are currently entering the clinic and may provide more potent or less toxic inhibition of EWS–FLI1 due to differences in effects on DNA damage pathways (Guirouilh-Barbat et al., 2008).
    PARP inhibitors There is a growing enthusiasm in the Ewing sarcoma community to evaluate poly ADP ribose polymerase (PARP) inhibitors in the clinic. This is the direct result of two manuscripts that suggest an inherent sensitivity of ES cells to PARP inhibition (Brenner et al., 2012, Garnett et al., 2012). In the first study, 639 cell lines were evaluated to determine a relationship between sensitivity to 130 different drugs as a function of 64 fully sequenced cancer genes, genome wide analysis of copy number, and expression profiling. Among the most statistically significant relationships was the relationship between EWS–FLI1 expression and sensitivity to the PARP inhibitor AZD2281 (olaparib) (Garnett et al., 2012). This relationship approximated the statistical significance of the known relationship between imatinib and nilotinib and BCR-ABL as well as PLX4720 and SB590885 and mutation of BRAF. The authors went on to show a relative increased sensitivity of some but not all ES cell lines to olaparib with a geometric mean IC50 of 4.7μM relative to 64μM for the 291 other cell lines. The other manuscript utilized a candidate gene approach to evaluate olaparib in Ewing sarcoma cells (Brenner et al., 2012). The authors again showed increased sensitivity of 3 ES cell lines to olaparib as opposed to an osteosarcoma and rhabdomyosarcoma cell line. In addition, EWS–FLI1 gene transfer experiments seemed to increase the sensitivity to olaparib, an effect that was recapitulated in the other manuscript (Brenner et al., 2012). Of note, the drug was not effective as a single agent in xenograft experiments. However, this experiment was performed with the goal of demonstrating synergy so the drug may have single agent activity at higher doses. In addition, a combination with temozolamide showed an impressive regression of tumor growth (Brenner et al., 2012). The challenge in moving PARP inhibitors forward lies in understanding the biology behind these effects, the context that determines sensitivity, as well as determining the optimal combination therapy for clinical translation. It has been known since the early 1990s that Ewing sarcoma cells express high levels of PARP mRNA, protein and have an inherently high PARP activity potentially related to an increase in copy number (Prasad et al., 1990). This increased PARP activity led to the demonstration that inhibition of PARP with chemical tool compounds sensitized ES cells to ionizing radiation (IR) (Prasad et al., 1990). Subsequent studies confirmed the high level of PARP expression and showed that the promoter of PARP1 contained several ETS binding sites (Soldatenkov et al., 1999). However, it was shown that in A4573 Ewing sarcoma cells, PARP expression was driven by the FLI1 family member ETS1 and EWS–FLI1 actually suppressed PARP promoter activity and caused a minimal decrease in PARP expression (Soldatenkov et al., 1999, Soldatenkov et al., 2002). In addition, this report showed that silencing ETS1 with an antisense DNA, decreased PARP expression and was associated with resistance to the DNA damaging agent etoposide, while the suppression of EWS–FLI1 caused a minor increase in PARP that nonetheless sensitized cells to etoposide, presumably by interfering with other DNA damage pathways (Soldatenkov et al., 2002). This is in contrast to recent reports that show that in RD-ES cells PARP expression is driven by EWS–FLI1 and siRNA silencing of EWS–FLI1 markedly decreases PARP expression (Soldatenkov et al., 2002). Since both studies evaluated both promoter activity and total protein expression, there are clearly yet to be determined indirect effects that mediate the relationship between EWS–FLI1 and PARP.