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Cellular and Molecular Biology 14: Gene Expression Profiling

Abstract #865

Integrative analysis of genomic RNA expression data from in vitro and in vivo models of TGF-beta receptor kinase inhibitors to identify novel informative biomarkers of TGF-beta signaling

Lilly Systems Biology Pte, Ltd. Singapore, Singapore, Singapore, Eli Lilly and Company, Indianapolis, IN, Eli Lilly and Company, Erl Wood, United Kingdom

Overexpression of TGF-ß is involved in the pathogenesis of cancer and fibrosis. The dihydropyrrolopyrazole series of small molecules, including the clinical candidate LY2157299, are potent TGF-ß type I receptor kinase inhibitors with the ability to reverse TGF-ß mediated biological activity in a variety of cellular assays. Detailed characterization of these compounds in vivo has demonstrated that they are bioavailable, inhibit the type I receptor kinase in vivo. Pre-clinical target modulation data in mouse and rat models, using phospho-SMAD2 as an immediate downstream biomarker of target modulation, has allowed development of PK/PD models that will guide clinical development of this class of inhibitors for cancer. We looked here to identify more distal effects of TGF-ß signaling and its inhibition across multiple models. Whole genome microarray expression were analyzed for the effects of TGF-ß signaling and inhibition of TGF-ß RI by LY2157299 in Calu6 cells, revealing many transcripts with expression dependent on TGF-ß stimulation and reversed in a dose dependent fashion by LY2157299. These data were analyzed together with corresponding data from an in vivo Calu6 xenograft tumor growth model to identify genes whose expression is consistently and significantly affected by compound administration both in vitro and in vivo. Numerous genes previously known to be affected by TGF-ß signaling, such as SMAD7, TMEPAI, and JUNB, are identified in this analysis. Further confirmation, and potential utility as translational biomarkers, is provided by examining expression data from ex-vivo PBMCs stimulated with TGF-ß in the presence or absence of LY2157299. Integrative analysis of these data shows how biomarker discovery can be integrated from in vitro discovery through preclinical PK/PD models and into potential clinical utility.