Identification of new targets and development of new tracers for gastrointestinal stromal tumors (GIST) based on gene array data and in silico modelling

Objectives Purpose of this study was to search for new potential targets for GIST based on gene array data of patients' tumor probes and develop new tracers using in silico modeling.

Methods 36 patients with GIST were included in the study. Samples of the tumor tissue were obtained by surgery. Samples from the normal colon served as reference. The GenePET program, developed by our group, was used for preselecting differentially expressed receptor active genes for GIST by the use of keywords. Moreover, the Mann-Whitney test value and ratio of tumor/reference tissue was applied on the preselected genes and was used for identification of possible targets, such as genes controlling receptor with high expression. At last, computational drug design methods were used to select possible substrates for the target, including generation of 3D pharmaceutical structure for the target using Fugue (NIBIO, Cambridge), identification of binding pocket using known ligands as well as achievement of new ligands by virtual screening with a dedicated multistep procedure.

Results 33 genes controlling receptors with high expression were identified by GenePET. Among them, integrin alpha V beta 3 possesses the highest Mann-Whitney value and gene-expression (Figure 1). By trial docking and structure-based optimization, we found a new ligand with better scores of docked poses compared with those known ligands (Figure 2). It should be noted that success of this method depends on the sequence identity between the target and template protein in the ligand-binding pocket.

Conclusions The combination of GenePET and virtual screening provides new capabilities for the discovery of new ligands for known receptors. In reverse, the GenePET program will further identify possible targets for these new ligands