Fibroblast Growth Factor Receptor 4 in Glioblastoma

Glioblastoma represents the most frequent and aggressive primary brain tumor with very poor prognosis. As also the currently used standard therapy with concomitant radiation and chemotherapy is only of limited activity, novel therapeutic approaches against this deadly disease urgently need to be developed. During the last decade, systemic cancer therapy made an important and successful development towards the use of targeted agents specifically interacting with molecular drivers of the respective cancer types. Unfortunately, in case of glioblastoma these novel approaches turned out to be of limited benefit. Also targeting of receptor tyrosine kinases known to be hyperactivated in this malignancy, like the epidermal growth factor receptor (EGFR) driving malignant growth, were widely ineffective. Besides EGFR, also fibroblast growth factor receptors (FGFR) are known to support glioblastoma development by contributing to blood supply and stemness of the disease. This project should clarify whether one of these high affinity FGFR, namely FGFR4, represents an innovative target for glioblastoma therapy. The underlying hypothesis is based on preclinical data from our own group (Head: Prof. Walter Berger) demonstrating that a blockade of FGFR4 specifically interferes with the three-dimensional growth of glioblastoma models and with tumor formation in murine transplantation models. While blockade of EGFR and FGFR1 mainly inhibited glioblastoma cell growth in culture (in vitro) even to a greater extent than FGFR4, the in vivo situation was opposite. Genetic blockade of FGFR4 in the living organisms was more effective than that of EGFR and FGFR1 and inhibited tumor formation completely. The submitted proposal aims to extensively characterize - by using an extended collection of surgical specimens, tumor cell cultures and preclinical animal models - the molecular factors underlying the tumor-supporting effects of FGFR4 in glioblastoma. Human tumor sections and biopsies will be investigated regarding the expression of FGFR4 and other oncogenic receptor tyrosine kinases like EGFR as well as known biomarkers for glioblastoma aggressiveness and data compared to clinical parameters including course of disease and therapy response. A special focus will be laid on gliosarcoma, a highly aggressive subgroup of glioblastomas, which demonstrated in our preliminary analyses frequently very high FGFR4 expression levels. Using cell and transplantation models with altered FGFR4 expression (overexpression and knock-down), the contribution of FGFR4 to migration, invasion, stemness and therapy resistance will be elucidated. Additionally, we will analyse whether a pharmacological blockade of FGFR4 by specific small molecule inhibitors is active in preclinical glioblastoma and gliosarcoma models. Moreover, it will be tested whether a combination of FGFR4 inhibitors with the clinically applied standard therapy for glioblastoma is beneficial and leads to enhanced anticancer activity. In summary, this project will comprehensively test the feasibility of a promising novel targeted therapy approach for human glioblastoma.

Primary brain tumors, developing - in contrast to metastases - directly from brain tissue, are often characterized by a highly invasive growth and a dismal patient prognosis. This holds especially true for the most frequent and aggressive adult brain cancer glioblastoma, but also for certain pediatric gliomas and ependymomas. Tumor cells often depend on proliferation and survival signals transmitted by growth factors and their respective receptors. While in healthy tissues growth factor receptors are often activated by growth factors secreted by adjacent tissues, tumor cells start to produce their own growth factors rendering them independent from the surrounding tissues. Additionally, growth factor receptors are frequently genetically altered and constantly activated, allowing autonomous growth and survival. One important example is the "epidermal growth factor receptor" (EGFR), which is frequently mutated in glioblastoma, thus supporting tumor growth, survival and therapy resistance. Unfortunately, inhibition of EGFR, as successfully used in treatment of lung cancer, did not induce longer-lasting tumor control in glioblastoma. One reason is the redundancy of growth factor receptor signals, allowing other signal molecules to take over the activity of the inhibited receptor. Consequently, we have investigated in this project by diverse data- and laboratory-science approaches another powerful, tumor-promoting growth factor system, namely the fibroblast growth factors and their respective four receptors (FGFR1-FGFR4) and their role in primary brain tumor aggressiveness. While the primary focus was on adult glioblastoma, we extended the project aim also to pediatric brain tumors with dismal prognosis. Besides the analyses of own and internationally available big data sets, we have also investigated multiple two- and three-dimensional cancer models, partly established from well characterized patient material. Based on promising preliminary data, our main focus concerned the in glioblastoma widely unexplored FGFR4 as compared to other FGFR family members. These oncogenic signal molecules were not only characterized concerning their role in cancer development and progression, but also as potential therapy targets. Indeed, we could identify a highly-aggressive subgroup of glioblastomas, whose malignant growth depends on FGFR4 signals. FGFR4 is interacting in these cancers with a group of cell adhesion molecules, termed integrins, thus supporting cancer cell adhesion and migration. The combined inhibition of FGFR4 and defined integrins led to loss of glioblastoma cell adhesion and massive cell death induction. Concerning pediatric brain tumors, we identified an even more widespread contribution of several FGF/FGFR molecules to tumor development and progression of several glioma and ependymoma subtypes, and selected FGFR members were suggested as therapeutic targets in this project. In a few cases, a first-of-its-kind clinical response to FGFR inhibition could be reported. Hence, the results of this project do not only help to better understand the molecular drivers of primary brain tumors but also to identify novel therapeutic strategies.