Abstract 5244: Preclinical, real-time assessment of early pharmacodynamic effects for the IGF-1R/IR inhibitor OSI-906 by [18F]-FDG-PET

Abstract

Abstract The insulin-like growth factor-1 receptor (IGF-1R) and insulin receptor (IR) are transmembrane receptor tyrosine kinases that serve as key regulators of the IGF signaling axis. Activation of IGF-1R and IR results in proliferative and antiapoptotic effects via the ERK and PI3K/AKT pathways. Activated IGF-1R and IR also directly affect glucose metabolism by decreasing gluconeogenesis, increasing glycogen formation and increasing translocation of GLUT transporters, thereby increasing overall glucose uptake in tissues. Dysregulated IGF-1R/IR signaling has been implicated in many human cancers and has been implicated in resistance to anticancer therapies including cytotoxic chemotherapy, hormonal agents and radiation therapy. IGF-1R/IR overexpression has been demonstrated in several tumor types including breast, prostate, lung, ovarian and colon cancers. Moreover, increased activation and overexpression of IGF-1R/IR is associated with an increased propensity for invasion and metastasis correlating with poor survival. Consequently, IGF-1R and IR have been identified as attractive targets for the generation of novel anticancer agents. OSI-906 is a potent and selective dual inhibitor of IGF-1R/IR and is currently in clinical development. The radiotracer [18F]-FDG is used clinically to stage disease or monitor treatment response by virtue of measuring glucose uptake as a surrogate for metabolic activity in tumors. Since IGF-1R and IR signaling directly affect glucose metabolism we evaluated the utility of [18F]-FDG-PET as a potential means to non-invasively monitor pharmacodynamic (PD) effects for OSI-906. In vitro the IGF-1R/IR positive cell line, H292, responded rapidly to OSI-906 treatment by significantly reducing uptake of 3H-glucose. Radiotracer uptake was inhibited in a dose dependent manner and occurred within minutes of drug treatment correlating with inhibition of the IGF-1R/IR pathways and other downstream signaling events. In vivo xenografts bearing the same cell line demonstrated significantly reduced uptake of [18F]-FDG at 2 and 4 hours post treatment which correlated with substantial (>80%) target inhibition of both phospho-IGF1-R and phospho-IR in the tumor lysates. Western blot analysis of in vivo tumor lysates confirmed significant inhibition of phospho-AKT and other markers associated with altered glycolysis. In contrast, in the IGF-1R/IR-negative H441 xenograft model no significant change in uptake of [18F]-FDG was observed over the same time course. Our data indicate that [18F]-FDG-PET may serve as a rapid, non-invasive PD marker for OSI-906 in the clinical setting where accurate assessment of PD effects is often limited by the lack of readily accessible tumor samples. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5244.