Dual-Targeting Of Igf-1r And Erbb3 Pathways In Ewing'S Sarcoma Cellular Models With Istiratumab (Mm-141), A Bispecific, Tetravalent Monoclonal Antibody

Abstract Ewing’s sarcoma family tumors (ES) are aggressive tumors that often present as metastatic in bone and soft tissue and predominantly affect adolescents and younger adults. Current treatment for ES includes surgical resection followed by loco-regional radiotherapy and chemotherapy. Survival rates for patients with metastatic disease continue to offer a particularly difficult clinical challenge, with a five-year survival rate of 20-30% for these patients. ES is primarily a genetic disease caused by fusion between the 5’ segment of the Ewing sarcoma breakpoint region 1 gene (EWSR1) on chromosome 22 and the 3’ portion of Friend leukemia virus integration site 1 (FLI1) on chromosome 11. Fusions of EWSR1 and other ETS transcription factors result in dis-regulated transcription factors which promote malignant progression of ES tumors. Recent studies have shown that most ES cell lines and clinical samples express IGF-1R. Importantly, an activated IGF-1R pathway appears to be a prerequisite for malignant transformation by the EWS-FLI1 translocation, presumably via activation of the PI3K-AKT and MAPK pathways. These findings have led to the preclinical and clinical evaluation of multiple IGF-1R-targeted therapeutics with varying results. Clinical experience with anti-IGF1R targeting therapies has demonstrated striking anticancer activity in minor subsets of patients with ES. Importantly, the paucity of a clinically useful biomarker to select patients continues to hinder IGF-1R drug development in ES. Istiratumab is an investigational, bi-specific, monoclonal antibody that acts as a tetravalent inhibitor of PI3K/AKT/mTOR, a major pro-survival pathway tumor cells use as a resistance mechanism to anticancer therapies. Istiratumab is designed to interfere with this pathway by blocking ligand-induced signaling through the IGF-1R and ErbB3 receptors, based on findings that ErbB3 activation mediates resistance to the IGF-1R blockade. We will present data in multiple ES models demonstrating the importance of both IGF-1R and ErbB3 in this disease as a mechanism of growth and resistance. Furthermore, preclinical xenograft studies demonstrate that the combination of istiratumab with an irinotecan-based chemotherapy regimen offers significant benefit over chemotherapy alone. These studies suggest that clinical evaluation of istiratumab in ES is warranted. Citation Format: Isabel Yannatos, Adam Camblin, Zhenhua Li, Michael Curley, Gege Tan, Chrystal U. Louis, Vasileios Askoxylakis, Greg Finn, Birgit Schoeberl, Rachel Nering. Dual-targeting of IGF-1R and ErbB3 pathways in Ewing’s Sarcoma cellular models with istiratumab (MM-141), a bispecific, tetravalent monoclonal antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 521. doi:10.1158/1538-7445.AM2017-521