Abstract 1208: Elucidating possible functional implications of osteosarcoma risk-associated genetic level alterations in IGF2R

Abstract

Abstract To address the need for novel osteosarcoma (OS) treatment regimens with greater efficacy and less toxicity, attention has been focused on developing antibodies that target components of the insulin-like growth factor (IGF) pathway, particularly insulin-like growth factor 1 receptor tyrosine kinase (IGF1R). IGF1R and its two ligands, insulin-like growth factor 1 (IGF1) and insulin-like growth factor 2 (IGF2), are known to be over-expressed in several cancers including OS and have roles in regulating cellular growth and proliferation. Clinical trials of IGF1R-inhibiting antibody therapies in OS, however, have returned mixed results. Studies aimed at elucidating the biologic basis of this differential clinical sensitivity to IGF1R-targeting therapeutic agents are currently underway. Interestingly, recent studies from our lab show that IGF2R is consistently over-expressed, relative to other known transmembrane receptors, on the cell surface, across 4 standard and 10 patient-derived OS cell lines. Coupled with results from concurrent experiments suggesting a lack of IGF1R copy number amplification in the majority of tested patient-derived OS samples and xenograft models, we chose to focus our next set of studies on IGF2R_aiming to characterize significant genetic variations within this gene and any functional implications, thereby elucidating the link, if any, between IGF2R's mutational status and its cell surface expression in OS. Relative quantification studies, done via real-time PCR, demonstrated variable IGF2R gene expression across 27 patient-derived OS samples, 4 xenograft models, and 4 standard cell culture (serum-starved) lines. Using the CaCo-2 cell line as the calibrator, 12 out of 27 patient-derived OS samples showed increased IGF2R gene expression, while none of the xenograft models or the standard OS cell lines did. Ongoing studies will examine the relationship between genetic level alterations in IGF2R and its patterns of expression; common IGF2R SNPs will be genotyped, first in the four available OS xenograft models. Findings will be correlated with known patterns of clinical response/sensitivity to IGF1R-targeted therapy tested on these models. The same SNPs will then be genotyped in the patient-derived OS samples and standard cell culture lines. Depending on the results obtained from these initial studies, further experiments can be designed to sequence/genotype other suspect coding regions on the IGF2R gene that may contain functionally significant mutations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1208. doi:10.1158/1538-7445.AM2011-1208