FGF/FGF-rezeptors as therapeutic targets in solid tumors

Fibroblast growth factors (FGFs) are a large family of polypeptides which transduce signals through binding to high affinity transmembrane tyrosine kinase receptors (FGFRs). FGFs and FGFRs play crucial roles in embryonic, fetal, and postnatal development, as well as wound healing and tissue maintenance. However, deregulation of FGF/FGFR signalling is also involved in a variety of pathological conditions, most notably in cancer. Previous studies on the role of FGFs and FGFRs in tumor growth mainly focused on neuronal tumors, melanoma, prostate and pancreatic cancer, while less is know on colon, liver, and lung cancer. Principal aim of the projects first part is to establish a comparative expression profile of FGF/FGFR molecules in human colon, liver, and lung cancer and to identify candidates for a targeted therapy approach. A special focus will be laid on the comparison of the in vitro and in vivo situation with regard to the expressed molecules (including isoforms and splice variants), and possible autocrine but also paracrine interactions. Expression profiles will be compared to tumor histology, invasive and metastatic potential, and other clinicopathological features. In the second part of the project, the role of specific FGF/FGFR signals in tumor cell growth, cell survival, and invasive potential in vitro as well as in the SCID mouse model will be analyzed. For that purpose selected FGF and/or FGFR molecules or their interactions will be inhibited in human tumor cell lines using appropriate techniques (small molecule inhibitors, siRNA, dominant-negative constructs). Those FGF/FGFR signals demonstrated to be essential for the malignant growth of the investigated tumor types will be further evaluated in vitro with respect to their feasibility as potential therapy targets for colon, liver, and lung cancer. In this respect, possible synergistic effects of FGF/FGFR inhibition with that of other oncogenic receptor tyrosine kinases and/or conventional chemotherapeutics will be analyzed. Solid tumors in colon, liver, and lung are together responsible for up to 40% of the cancer deaths world wide mainly due to the limited therapeutic possibilities at the advanced stage. This study will allow estimating whether members of the FGF/FGFR growth factor system represent feasible targets for the development of new therapeutic strategies for these devastating malignancies.

Aim of the project P170630 was to evaluate inhowfar fibroblast growth factors (FGF) and their high-affinity receptor tyrosine kinases (FGFR) may represent promising therapeutic targets in case of widely therapy resistant carcinomas including non-small cell lung cancer (NSCLC), liver cancer (hepatoma) and colon cancer. The FGF/FGFR system constitutes one of those signal systems guiding growth processes during embryonic development. They are also essential for wound healing and tissue homeostasis in the adult organism. Unfortunately pathological hyperactivation of this system due to overexpression and/or mutational events can lead to malignant cell growth and thus cancer. Consequently the inhibition of these hyperactivated growth signals is a potent strategy for anticancer treatment and indeed for example inhibitors of the epidermal growth factor receptor (EGFR) are already in clinical use for therapy of several disseminated carcinomas. In contrast, the FGF/FGFR signal is widely unexplored. One explanation might lie in the complexity of the system with 22 FGF and 4 FGFR genes the latter generating multiple mRNA variants due to alternative splicing. To meet the complexity of the system our project started with a screening approach detecting all the multiple mRNA molecules by RT-PCR approaches. Supporting our working hypothesis we indeed found multiple FGF and FGFR molecules overexpressed in all three tumor types suggesting the presence of autocrine growth loops. FGF/FGFR-mediated growth signals might thus represent suitable therapeutic targets in the investigated tumor entities. This hypothesis was supported by the next experiments demonstrating that genetic or pharmacological inhibition of FGF/FGFR- mediated signals (by dominant-negative receptor constructs and small molecule inhibitors) induced growth arrest and/or programmed cell death in carcinoma cells. For example in NSCLC the blockade of FGFR1 was particularly effective. Additionally to external FGFR inhibition, we could also show that the expression of internal inhibitors of FGFR signals, the Sprouty proteins, is strongly reduced in NSCLC cells. Both, blockade of FGFR by a dominant- negative transgene and re-expression of Sprouty proteins not only inhibited NSCLC growth in vitro but also tumor formation in the SCID mouse. Furthermore FGFR blockers exerted synergistic antitumor activity with certain types of chemotherapy and especially with EGFR inhibitors. Comparable to NSCLC, in colon cancer an autocrine/paracrine growth loop was defined involving FGF18 and FGFR3. Moreover, FGFR4 could represent a marker protein in liver cancer. The obtained data within project P17630 initiated a consecutive project funded by the FWF and currently starting which aims to further define the signal pathways involved in the oncogenic functions of FGF/FGFR. The project P17630 moreover initiated several cooperations with the pharmaceutical industries in order to develop FGF/FGFR inhibitors as cancer therapeutics. In summary the data generated within this project demonstrate that FGF/FGFR-mediated signals are promising therapeutic targets for the notoriously therapy resistant carcinomas of lung, colon and liver. These tumors cause together about 40% of all cancer deaths worldwide.