Institute of Information Science Academia Sinica
Topic: TIGP -- Drug discovery via drug repurposing
Speaker: Prof. Chi-Ying F. Huang (Institute of Biopharmaceutical Sciences, National Yang-Ming University)
Date: 2013-03-12 (Tue) 16:00 – 17:10
Location: Auditorium 106 at new IIS Building
Host: TIGP Bioinformatics Program

Abstract:

The availability of Connectivity Map offers an alternative tool in the drug discovery arena, and the use of this tool could promote Food and Drug Administration approval of old drugs for unmet clinical needs. I will discuss examples to use this tool for drug discovery. Cancer stem cell (CSC) theory has drawn much attention, with evidencesupporting the contribution of stem cells to tumor initiation, relapseand therapy resistance. To screendrugs that target CSCs to improvethe current treatment outcome and overcomedrug resistancein lung cancer patients. Weused publicly available embryonic stem cell and CSC-associatedgene signatures to query the Connectivity Map for potential drugs that can, at least in part, reverse the gene expression profile of CSCs. High scoreswere noted for several phenothiazine-like anti-psychotic drugs, includingtrifluoperazine. We then treated lung CSCs with different EGFR mutation status with trifluoperazineto examine its anti-CSC properties. Lung CSCs resistant to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) or cisplatin were treated with trifluoperazineplus gefitinib or trifluoperazineplus cisplatin. Animal models were used for in vivovalidation of the anti-CSCeffect and synergistic effect of trifluoperazinewith gefitinib. We demonstrated that trifluoperazine inhibited CSC tumor spheroidformation and down-regulated the expression of CSC markers (CD44/CD133). Trifluoperazineinhibited Wnt/β-catenin signaling in gefitinib-resistant lung cancer spheroids. Thecombination of trifluoperazine witheither gefitinibor cisplatinovercamedrug resistancein lung CSCs. Trifluoperazineinhibited the tumor growth and enhanced the inhibitory activity of gefitinib in lung cancer metastatic and orthotopic CSC animal models.Using in silico drug screening via Connectivity Map followed by empirical validations, we repurposed an existing phenothiazine-like anti-psychotic drug, trifluoperazine, as a potentialanti-CSC agentthatcould overcome EGFR-TKI and chemotherapy resistance.