Abstract 1802: IGF-1R inhibition as a novel therapeutic strategy for small cell lung cancer

Abstract

Abstract Small cell lung cancer (SCLC), which makes up approximately 15% of all lung cancer cases, is characterized by short responses to standard chemotherapy and a median survival duration of less than one year. New therapies are critically needed to improve the outcome for patients with this disease. Signaling through the insulin-like growth factor 1 receptor (IGF-1R) leads to activation of the PI3K-AKT and MAP kinase pathways, resulting in inhibition of apoptosis and stimulation of proliferation. The IGF-1R pathway is commonly upregulated in SCLC. Recent evidence suggests that inhibition of IGF-1R may be a potential treatment strategy for many types of cancer, including SCLC. We sought to characterize the relative sensitivity of SCLC cell lines to a novel IGF-1R tyrosine kinase inhibitor, OSI-906, identify predictive biomarkers of sensitivity, and evaluate the efficacy of OSI-906 in vivo on SCLC cell line xenografts and primary patient xenografts as a single agent and in combination with etoposide. We assessed the sensitivity of a panel of 16 SCLC cell lines to OSI-906. Approximately one third of these cell lines were highly sensitive to OSI-906, with an IC50 < 1 μM, as measured by the MTS cell proliferation assay. Treatment with increasing doses of OSI-906 resulted in dose dependent inhibition of phosphorylated IGF-1R and phosphorylated AKT in both sensitive and resistant cell lines, suggesting that while the IGF-1R signaling pathway is intact in resistant cell lines, they rely on other signaling pathways for survival. Expression profiling of our panel of cell lines for components of the IGF-1R pathway including IGF-1R, insulin receptor (IR), and receptor ligands (IGF-1 & IGF-II) did not suggest a simple correlation between receptor/ligand expression and sensitivity to OSI-906. Interestingly, OSI-906 sensitive cell lines appear to express lower levels of phosphorylated ERK at baseline compared to resistant cell lines. In addition, phospho-ERK is not inhibited by OSI-906 and is upregulated in response to treatment in some resistant cell lines. We tested the efficacy of OSI-906 alone and in combination with etoposide in vivo using an H187 cell line xenograft model and two primary patient xenograft models. OSI-906 alone resulted in approximately 50% tumor growth inhibition in H187 xenografts and 30% inhibition in the primary patient xenograft models compared to mock treated animals. There was no evident synergy with etoposide in any of these models. Our preliminary data support that IGF-1R inhibition may be a viable treatment strategy for a subset of SCLC. Identification of the subset that will respond to this therapy may be more complex than screening for expression IGF-1R pathway components. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1802. doi:1538-7445.AM2012-1802