Abstract C103: Sarcoma cell line sensitivity towards approved oncology drugs and investigational agents identifies distinct patterns of response which can be interrogated with associated gene expression.

Abstract

Abstract Sarcomas represent a heterogeneous group of cancers with significant unmet medical needs. We have examined the response of 64 sarcoma cell lines to treatment with 103 approved oncology drugs (available from The NCI/DTP Open Chemical Repository) and 420 agents in the investigational agents library, using inhibition of proliferation as an endpoint. Cells were exposed to compounds at varying concentrations (10μM to 1.5nM) for 96 h and the effect of compound on cell viability was monitored using Alamar Blue. From curve fitting algorithms we determined the IC50 values of each agent on the cell lines. Adult sarcomas comprise 23% of this sarcoma panel and have a different spectrum of sensitivities to selected agents. They were generally more chemoresistant than the pediatric lines, although they are marginally more sensitive to MEK inhibitors. Synovial tumor cell lines were an exception, being sensitive to several classes including dasatinib and Bcr-abl inhibitors. Ewings tumors tend to be the most sensitive pediatric group responding to Parp-1 and IGF-1R inhibitors. Overall, gene, and to a lesser extent, miRNA profiles from the adult sarcoma's were more similar to the profiles of normal, non-tumor cells, than the pediatric tumors, and this lack of genotypic divergence may underlie the insensitive phenotype observed in the sarcoma panel. From an analysis of sensitivity clustering, IGF-1R inhibitors (8), cluster with some of the AKT (8) and ALK (8) inhibitors. None of the cell lines have the EM4L-ALK translocation, thus we investigated the genes associated with sensitivity to these three mechanisms. Dendrograms identified a close relationship between the IGF-1R and AKT inhibitors, based on the gene expression patterns, while the ALK inhibitors were quite distinct, substantiating known pathways of IGFR-1R signaling through AKT, but unrelated to ALK. Genes associated with ALK sensitivity included several from gluconeogenesis, and potential activation of the MYC response. In contrast, genes associated with AKT and IGF1R sensitivity are focused around FOXO1 transcription factor. Interestingly, the PAX-FOXO1 gene fusion is a hallmark of the aggressive alveolar rhabdomyosarcoma which are more sensitive to these agents than embryonal rhabdomyosarcoma. Thus the combination of drug sensitivity data, together with the gene and miRNA profiles may allow correlations in treatment efficacy that may point to new avenues for clinical development in sarcoma. Funded by NCI Contract No. HHSN261200800001E. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C103. Citation Format: Anne Monks, David Evans, Thomas Silvers, Rene Delosh, Julie Laudeman, Chad Ogle, Russell Reinhart, Michael Selby, John Connelly, Annamaria Rapisarda, Mark Kunkel, Joel Morris, Kazimierz Wrzeszczynski, Eric Polley, Beverley Teicher. Sarcoma cell line sensitivity towards approved oncology drugs and investigational agents identifies distinct patterns of response which can be interrogated with associated gene expression. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C103.