Transcription Factor-Binding Site Identification and Enrichment Analysis.

Transcription factors orchestrate complex regulatory networks of gene expression. A better understanding of the common transcription factors, and their shared interactions, among a set of coregulated or differentially expressed genes can provide powerful insights into the key pathways governing such expression patterns. Critically, such information must also be considered in the context of the frequency in which a transcription factor is present in a properly selected background, and in the context of existing evidence of gene and transcription factor interaction. Given the vast amount of publicly available gene expression data that can be further scrutinized by the user-friendly analysis tools described here, many useful insights are assuredly to be revealed. The proceeding methods for application of the analysis tool CiiiDER for transcription factor-binding site identification, enrichment analysis, and coregulatory factor identification should be applicable to any dataset comparing differential gene expression in response to various stimuli and gene coexpression datasets. These methods should assist the researcher in identifying the most relevant regulators within a gene set, and refining the list of targets for future study to those which may share biologically important regulatory networks.

Evaluation of TAK-264, an Antibody-Drug Conjugate in Pancreatic Cancer Cell Lines and Patient-Derived Xenograft Models.

BACKGROUND: Antibody-drug conjugates (ADCs) are an emerging technology consisting of an antibody, linker, and toxic agent, which have the potential to offer a targeted therapeutic approach. A novel target recently explored for the treatment of pancreatic cancer is guanylyl cyclase C (GCC). The objective of this study was to determine the anti-tumorigenic activity of TAK-264, an investigational ADC consisting of an antibody targeting GCC linked to a monomethyl auristatin E payload via a peptide linker. METHODS: The antiproliferative effects of TAK-264 assessed in a panel of eleven pancreatic cancer cell lines. Additionally, ten unique pancreatic ductal adenocarcinoma cancer patient-derived xenograft models were treated with TAK-264 and the efficacy was determined. Baseline levels of GCC were analyzed on PDX models and cell lines. Immunoblotting was performed to evaluate the effects of TAK-264 on downstream effectors. RESULTS: GCC protein expression was analyzed by immunoblotting in both normal and tumor tissue; marked increase in GCC expression was observed in tumor tissue. The in vitro experiments demonstrated a range of responses to TAK-264. Eight of the ten PDAC PDX models treated with TAK-264 demonstrated a statistically significant tumor growth inhibition. Immunoblotting demonstrated an increase in phosphorylated-HistoneH3 in both responsive and less responsive cell lines and PDAC PDX models treated with TAK-264. There was no correlation between baseline levels of GCC and response in either PDX or cell line models. CONCLUSION: TAK-264 has shown suppression activity in pancreatic cancer cell lines and in pancreatic PDX models. These findings support further investigation of ADC targeting GCC.