Project 5

1. Applicant

2. Topic

Identification and molecular targeting of signaling pathways in malignant melanoma

3. Short summary

The aim of the presented project is the identification of signaling pathways active during melanoma development and progression and design of new substances for functional interference with these pathways. For this purpose, a large-scale loss-of-function screen using a genome-wide RNAi library will be performed, followed by a molecular targeting approach of signaling molecules by individually synthesized inhibitor molecules. First, melanoma cells will be transduced with a pooled lentiviral shRNA library targeting all currently known genes. Stable transduction of cells will result in either slowdown of growth, apoptosis, or growth advantage of individual cell clones, with the subsequent loss or overrepresentation of the corresponding siRNAs. The resulting differences in siRNA patterns between cultures after RNA interference and selection and control cultures (siRNA transduced without positive or negative selection) will be analyzed by DNA microarray technology, using commercially available DNA microarrays. Modern bioinformatics will then be applied to identify relevant signaling molecules and pathways. Subsequently, newly identified pathways will be targeted by small molecule inhibitors, derived from an existing library of chemical inhibitors (indirubins), which will be modified for optimal interference with signal transduction and cell growth. Many of these had already been shown to target important cell signaling or cell cycle molecules. Together, the presented project could help to lay the foundation for an optimized molecular targeted therapy for malignant melanoma, with concurrent minimization of side effects on benign cells. We feel that the presented screening approach is ideally suited for a collaborative project such as presented by our consortium, since our findings may be validated using a plethora of different expertises within the consortium.

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