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Study Reexamines Role of IGF-1R As Therapeutic Target in Ewing Sarcoma

First author Alison O'Neill, then an undergraduate at Georgetown University and now a first-year medical student at Georgetown, and a team of scientists from Johns Hopkins, Boston Children's Hospital, Memorial Sloan-Kettering Cancer Center, and Georgetown's Lombardi Cancer Center (including senior author Dr. Jeffrey Toretsky), have found evidence that the insulin-like growth factor 1 receptor (IGF-1R) may require reevaluation as a therapeutic target in Ewing sarcoma (ES). The group’s findings, published online on January 29, 2013 in the open-access journal Sarcoma, contribute to a growing body of work that calls into question the longstanding high hopes for anti-IGF-1R therapy in light of the actual nature of IGF-1R’s role in Ewing sarcoma biology. The authors noted that IGF-1R has been the subject of more than 20 years of research as a potential therapeutic target in ES. These investigations have included the role of IGF-1R in the initiation of ES, in vitro and in vivo effects of blocking IGF-1R, and the expression of signaling components in patients with ES. 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 phase II studies showed objective response rates that ranged from 8 to 15%, with the vast majority being partial responses measured in weeks to months. The authors said that anti-IGF-1R therapy clearly benefits a subset of patients, and it will be essential to find markers to identify those patients most likely to respond. Although a substantial number of preclinical studies support an important role of IGF-1R in the tumorigenesis and continued survival of ES, IGF-1R lacks the strong characteristics of other tyrosine kinases successfully targeted in cancer, such as HER2, which is often expressed at levels reaching 2 million receptors per cell as a result of gene amplification in HER2-positive breast cancer, and BCR-ABL, a fusion protein resulting in a constitutively active tyrosine kinase in chronic myelogenous leukemia. The authors noted that, while their results support previous data that ES cell lines express IGF-1R, their findings also suggest that IGF-1R levels are low compared to those in cell lines transformed by IGF-1R. Ligand-binding displacement analysis showed that ES cell lines express between 13,000 and 40,500 IGF-1 receptors per cell; in an early report investigating the role of IGF-1R in transformation of mouse fibroblasts, wild type NIH-3T3 cells expressed 65,000 receptors per cell yet did not demonstrate anchorage independent growth. NWTb3 cells expressing 972,000 receptors per cell, however, reliably demonstrated colony formation in soft agar. The scientists said that their analysis of ES cell lines by flow cytometry supported their finding that IGF-1R is expressed at relatively low levels, with expression around two-log-fold lower than the levels detected in NWTb3 cells. Another recent report has demonstrated low IGF-1R levels in clinical samples, citing expression in only 20% of cases. The authors’ assessment of IGF-1R expression in patient tumors by ELISA similarly revealed low levels of the receptor in comparison with NWTb3 cells, showing anti-IGF-1R antibody binding between 4% and 20% of the positive control. Analysis of these tumors by immunohistochemistry showed the presence of IGF-1R on 5% to 100% of cells in each sample. However, the IGF-1R levels detected by ELISA did not reliably correlate with receptor levels measured by IHC. The authors noted that while both methods demonstrate the variability of IGF-1R expression in clinical specimens of ES, the lack of correlation in the results underscores the important difficulties of quantifying biological markers in patient tumors. In light of these observations, the researchers said that further efforts are warranted to clarify the claims that IGF-1R is overexpressed in ES, and that ES cells are truly addicted to IGF-1R signaling. Importantly, the authors noted that a recent study of the IGF-1R system as a prognostic indicator in ES reported that, contrary to prior assumptions, high expression of IGF-1 and IGF-1R predicted higher rates of event-free and overall survival, suggesting that the patients most in need of targeted therapies may not be in the subset of patients who will respond to IGF-1R treatment. Although the authors believe that valuable insights have been made into the role of the IGF-1R pathway in ES biology throughout the past two decades, they maintain that in reexamining the body of work on IGF-1R and ES in light of the clinical trials published to date, as well as new data assessing IGF-1R levels in ES cell lines and patient tumors, patterns are emerging that help us to understand the limited activity of this strategy in patients with ES. Although further development of approaches to target this complex system may be warranted, it is evident that targeting the IGF-1R is not, as was initially hoped, a straightforward solution to effectively treat this aggressive malignancy. 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. The poor prognosis for patients with ES indicates an urgent need for the development of targeted therapies and the importance of this study reexamining the utility of a longstanding target in ES therapeutic strategies. [Sarcoma article]