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  • Together the data suggests that more

    2019-09-10

    Together, the data suggests that more work needs to be done to establish the role of PARP inhibitors in Ewing sarcoma. As a single agent, there is some activity in Ewing sarcoma cell lines and a highly statistically significant relationship between olaparib sensitivity and EWS–FLI1 expression. However, the sensitivity does not occur in all the ES cell lines and predictors of sensitivity to PARP inhibition are clearly needed. There appears to be impressive activity in an ES xenograft when PARP inhibition is combined with temozolamide (Brenner et al., 2012). However, it is clear that combination of PARP inhibitors with other chemotherapeutic agents may substantially enhance myelosuppression and will require careful study to determine optimal dose and schedules (Kummar et al., 2011). It is clear that the activities of PARP are complex and it participates in multiple DNA repair pathways (reviewed in Wang et al., 2012). This biology is likely only further complicated by EWS–FLI1 that impacts the expression of multiple genes in various pathways. Therefore, careful studies of these agents in Ewing sarcoma will be required to allow for optimal utilization of these agents in treatment strategies.
    IGF signaling pathway inhibitors The importance of the IGF pathway to sarcoma biology including Ewing sarcoma has been the subject of decades of investigation. A number of important studies have established the importance of this pathway to the biology of Ewing sarcoma. In particular, IGF has been shown to mediate EWS–FLI1 driven malignant transformation of NIH3T3 Lithium Citrate pathway as measured by soft agar assay (Toretsky et al., 1997). EWS–FLI1 in turn drives expression of the IGF1R receptor and suppresses expression of the negative regulator of IGF, IGFBP3 (Prieur et al., 2004, Cironi et al., 2008, Herrero-Martin et al., 2009). In addition, recent work shows that EWS–FLI1 regulates a series of miRNAs that perturb multiple members of the IGF pathway (McKinsey et al., 2011). From a therapeutic standpoint, critical preclinical studies have established the sensitivity of ES cells to inhibition of IGF both in vitro and in animal models of Ewing sarcoma (Scotlandi et al., 1996, Scotlandi et al., 1998). These studies have established the importance of this pathway to the biology of Ewing sarcoma mitigating everything from angiogenesis to drug resistance to a variety of agents active in Ewing sarcoma including ET-743 (Hofbauer et al., 1993, Benini et al., 2001, Strammiello et al., 2003, Manara et al., 2005). In recent years, agents have become available to target this pathway in the clinic. In particular, work has been done to evaluate antibodies targeting the receptor, small molecule kinase inhibitors of the receptor and downstream target inhibitors such as mTOR. In the preclinical setting, these agents were successful at inhibiting Ewing sarcoma tumor growth both in vitro and in animal models (Scotlandi et al., 2005, Martins et al., 2006, Manara et al., 2007, Kolb et al., 2008, Kurmasheva et al., 2009, Houghton et al., 2010, Kang et al., 2010, Beltran et al., 2011, Kolb et al., 2011). In addition, the agents were linked to critical biological processes such as the establishment of blood vessels in the growing tumor and even experimental models of metastasis (Krishnan et al., 2006, Manara et al., 2007, Liu et al., 2010). Therefore, there was considerable excitement when these agents moved into the clinic. Early phase I work established the safety of the IGFIR antibodies in a variety of tumors, including Ewing sarcoma in children (Malempati et al., 2012). As the agents moved into phase II, the excitement led to robust accrual. In a study sponsored by the Sarcoma Alliance for Research through Collaboration (SARC) using a fully human IGFIR antibody, 115 Ewing sarcoma patients were accrued in 31 different institutions in just over two years (Pappo et al., 2011). Again dramatic responses were observed with this agent such as that seen in Fig. 2. However the overall response rates were in the range of 10–15%. A similar study with an alternative IGFIR antibody demonstrated response rates of 17% and again some dramatic responses were observed (Malempati et al., 2012).