Insulin-Like Growth Factor 1 Receptor as a Therapeutic Target in Ewing Sarcoma: Lack of Consistent Upregulation or Recurrent Mutation and a Review of the Clinical Trial Literature
The insulin-like growth factor 1 receptor (IGF-1R) has been considered an important therapeutic target in Ewing sarcoma (ES), generating a need to identify the subset of patients most likely to respond to IGF-1R inhibitors. We assessed IGF-1R expression in ES cell lines and patient tumors to understand the variable clinical responses to anti-IGF-1R therapy. Using ligand-binding displacement, we measured between 13,000 and 40,000 receptors per cell in ES cell lines. We used ELISA to quantify IGF-1R in patient tumors, which expressed 4.8%？？± 3.7 to 20.0%？？± 0.2 of the levels in a positive control cell line overexpressing IGF-1R. Flow cytometry showed markedly reduced IGF-1R expression in ES cell lines compared to a standard positive control cell line. The IGF1R gene was sequenced in 47 ES tumor samples and 8 ES cell lines; only one tumor sample showed a nonsynonymous mutation, R1353H, in a region with low functional impact. Finally, we assessed IGF-1R pathway activity in the ES stem cell (ESSC) population, to characterize its potential for resistance to anti-IGF-1R therapy, using Luminex technology. We found no significant differences in IGF-1R pathway activity between ESSCs and the total cell population. Overall, our findings suggest that IGF-1R as a therapeutic target in this sarcoma may require reevaluation. 1. Introduction Ewing sarcoma (ES) is a malignancy of the bone and soft tissue that occurs predominantly between the ages of 3 and 40 and is characterized by a (11; 22)( 24; 12) chromosomal translocation in 85% of cases, resulting in the oncogenic fusion protein EWS-FLI1. Despite aggressive multimodal treatment and advances in surgery, radiation, and chemotherapy, 30% of patients with localized disease at diagnosis and 75–80% of patients who present with metastases eventually die from their disease [1]. The poor prognosis for patients with ES indicates an urgent need for the development of targeted therapies. The insulin-like growth factor 1 receptor (IGF-1R) has been the subject of more than 20 years of research as a potential therapeutic target in ES [2]. These investigations have included the role of IGF-IR in the initiation of ES [3], in vitro and in vivo effects of blocking IGF-IR [4–8], and the expression of signaling components in patients with ES [9–11]. As a result of these data, patients with ES were thought to be ideal candidates for therapy directed towards the IGF-1R axis. ES patients were thus enrolled in early clinical trials of humanized monoclonal antibodies against IGF-1R with the expectation of significant antitumor effects. The
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