FGF/FGF-Receptors as Therapeutic Targets in Solid Tumors

The presented project is consecutive to the previous project P17630-B12 "Investigation of Fibroblast Growth Factors (FGF) and their high affinity receptors (FGFR) as candidate targets for therapy of human solid tumors" supported by the FWF since 2004. The original project had been planned for a time frame of three years including the salary for two PhD students. However, the grant by the FWF was approved for two years only and the funds reduced accordingly. The project has meanwhile generated interesting results, which are currently summarized in the project and 5 attached manuscript drafts. In order to be able to successfully finish the project, this "consecutive project" is now asking for further support for 18 months which would also allow the PhD students to successfully complete their thesis works. The main aim of the project is to investigate whether FGF/FGFR-mediated signals might represent feasible targets for therapeutic approaches against lung, colon, and liver cancer. As the initial screening phase of the project has been widely completed, promising FGF ligand and receptor molecules have been defined which warrant further analysis. Over-expression of several FGFs and FGFR splice variants were detectable in all investigated tumor types. These data suggest the presence of multiple autocrine/paracrine growth loops based on FGF/FGFR-mediated signals which might serve as therapeutic targets. Additionally, a blockade of FGFR signals by dominant-negative receptor molecules and/or the small molecule inhibitor SU5402 resulted in growth inhibition and/or apoptosis induction in cell lines from all investigated tumor types. These initial "proof-of-principle" data will now be further substantiated. The molecular interaction network underlying the oncogenic activity of the FGF/FGFR system will be dissected by analysing specific FGFR-downstream pathways. Additionally, in selected cell models the impact of FGF/FGFR inhibition by specific small molecule inhibitors on whole genome expression will be followed by microarray analysis. Therapeutic interventions will be extended to the cooperative inhibition of FGFR-derived signals with those of other receptor tyrosine kinases (RTKs). Moreover, small-molecule FGFR inhibitors (as for example PD166866) will be combined with the respective chemotherapeutic agents used in clinical chemotherapy of the investigated tumor types. The relevance of the in vitro data, demonstrating retardation of cancer cell growth and/or induction of apoptosis, will be further substantiated in vivo in the SCID mouse model as already designated in the original project. Based on the screening results obtained in vitro, the SCID mice experiments will be performed with the dominant-negative FGFR1 construct in case of NSCLC, with dominant-negative FGFR3 in colon cancer, and FGFR4 in hepatoma cell models. The respective experiments are currently initiated and will start soon but will requiring extension of the project time frame at least to the original three years. Summarizing, our preliminary in vitro data suggest that FGF/FGFR-mediated signals are promising intervention targets for the treatment of lung, colon, and liver cancer which all represent highly therapy-resistant tumor types. The current project will further define and substantiate the quality of this therapeutic approach and proof its applicability in vivo.

The presented project is consecutive to the previous project P17630-B12 "Investigation of Fibroblast Growth Factors (FGF) and their high affinity receptors (FGFR) as candidate targets for therapy of human solid tumors" supported by the FWF since 2004. The original project had been planned for a time frame of three years including the salary for two PhD students. However, the grant by the FWF was approved for two years only and the funds reduced accordingly. The project has meanwhile generated interesting results, which are currently summarized in the project and 5 attached manuscript drafts. In order to be able to successfully finish the project, this "consecutive project" is now asking for further support for 18 months which would also allow the PhD students to successfully complete their thesis works. The main aim of the project is to investigate whether FGF/FGFR-mediated signals might represent feasible targets for therapeutic approaches against lung, colon, and liver cancer. As the initial screening phase of the project has been widely completed, promising FGF ligand and receptor molecules have been defined which warrant further analysis. Over-expression of several FGFs and FGFR splice variants were detectable in all investigated tumor types. These data suggest the presence of multiple autocrine/paracrine growth loops based on FGF/FGFR-mediated signals which might serve as therapeutic targets. Additionally, a blockade of FGFR signals by dominant-negative receptor molecules and/or the small molecule inhibitor SU5402 resulted in growth inhibition and/or apoptosis induction in cell lines from all investigated tumor types. These initial "proof-of-principle" data will now be further substantiated. The molecular interaction network underlying the oncogenic activity of the FGF/FGFR system will be dissected by analysing specific FGFR-downstream pathways. Additionally, in selected cell models the impact of FGF/FGFR inhibition by specific small molecule inhibitors on whole genome expression will be followed by microarray analysis. Therapeutic interventions will be extended to the cooperative inhibition of FGFR-derived signals with those of other receptor tyrosine kinases (RTKs). Moreover, small-molecule FGFR inhibitors (as for example PD166866) will be combined with the respective chemotherapeutic agents used in clinical chemotherapy of the investigated tumor types. The relevance of the in vitro data, demonstrating retardation of cancer cell growth and/or induction of apoptosis, will be further substantiated in vivo in the SCID mouse model as already designated in the original project. Based on the screening results obtained in vitro, the SCID mice experiments will be performed with the dominant-negative FGFR1 construct in case of NSCLC, with dominant-negative FGFR3 in colon cancer, and FGFR4 in hepatoma cell models. The respective experiments are currently initiated and will start soon but will requiring extension of the project time frame at least to the original three years. Summarizing, our preliminary in vitro data suggest that FGF/FGFR-mediated signals are promising intervention targets for the treatment of lung, colon, and liver cancer which all represent highly therapy-resistant tumor types. The current project will further define and substantiate the quality of this therapeutic approach and proof its applicability in vivo.