Abstract IA18: A genomics approach to discover small-molecule perturbagens of cancer cells

Abstract

Abstract Aberrantly activated transcription factors and/or transcriptional programs play a critical role in the development of most cancers. In some cancers, the oncogenic transcription factors have been well characterized and result from either the ectopic activity of native transcription factors or from a chromosomal translocations driving overexpression or producing a mutant transcription factor. In other cases, the direct causative event of the aberrant transcriptional signature is unknown. Given their central role in cancer development, directly targeting transcription factors should be a propitious anti-tumor strategy. However, with the exception of the nuclear hormone receptor family of transcription factors, transcription factor oncoproteins have been largely refractory to conventional drug discovery approaches. While there have been advances in our ability to assess gene expression changes on a global scale, almost all existing approaches (e.g., microarrays, next generation sequencing) cannot be applied to large-scale screening endeavors due to cost and throughput limitations. Alternatively, the use of reporter systems and phenotypic endpoints (e.g., viability) has been challenged by false-positives. Recognizing these shortcomings, we developed an assay approach that allows interrogation of complex gene expression signatures in high-throughput format. Gene Expression-based High-throughput Screening (GE-HTS) allows for the assessment of expression of hundreds of endogenous genes in 384-well format, overcoming some of the challenges that are inherent in conventional target- and phenotype-based screening. We have used GE-HTS in small-molecule library screening endeavors to identify compounds that induce differentiation signatures in different cancer types in the absence of a known target, as well as alter the transcriptional activity of aberrant, oncogenic transcription factors. These compounds have served as leads for clinical trial development as well as tool compounds to further dissect biological mechanisms of disease pathogenesis. Citation Format: Kimberly Stegmaier. A genomics approach to discover small-molecule perturbagens of cancer cells [abstract]. In: Proceedings of the AACR Special Conference on Chemical Systems Biology: Assembling and Interrogating Computational Models of the Cancer Cell by Chemical Perturbations; 2012 Jun 27-30; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2012;72(13 Suppl):Abstract nr IA18.