The Gli project - Development of Gli-specific Inhibitors; Novel Way of Treating Cancer
Indication: Cancer
Targeted mechanism: Hedgehog (Hh) signaling pathways
Founding Researchers: Rune Toftgård, Matthias Lauth and Stephan Teglund, Karolinska Institutet
Background
Activation of the Hedgehog (Hh) signaling pathway has been shown to be involved in the development of cancers in various organs including prostate, lung, brain, skin, and breast. This activation is estimated to play a role in at least 25% of all cancer cases and is especially implicated in pancreatic cancers. The activity of this pathway contributes to proliferation of cancer cells and tumor growth. By developing drugs that can inhibit Hedgehog signaling one can treat cancers that until now have been resistant to conventional therapies.
Current status
In 2006, the GLI project was initiated at Actar together with researchers Rune Toftgård, Matthias Lauth and Stephan Teglund at the Department of Bioscience Karolinska Institutet. Professor Toftgårds research group have developed a cellular assay enabling screening for compounds that inhibit down-stream components of the Hedgehog signaling pathway. The assay is designed to pick out compounds that selectively inhibit the GLI transcription factors, and thereby inhibit transcription of Hedgehog target genes, without affecting general transcription. The screening assay is applied on Atcar´s diverse compound libraries to identify selective GLI inhibitors. The hit compounds, obtained from the screen, will then be evaluated in a set of cellular assays to address selectivity and toxicity. Compounds that pass the in vitro assessment will be evaluated by in vivo xenograft studies in rats with human cancer cells. Several hit compounds have been identified from the initial screen and are now being assessed in cellular evaluation to enable selection of compounds for the in vivo evaluation. The goal is to obtain candidate compounds that reduce tumour growth in vivo by 2009.