Defining the roles of fibroblast growth factor receptors on glioblastoma stem-like and non-stem cell populations

Glioblastoma is the most common type of brain cancer in adults, with no known cure. The complex mixture of different types of cancer cells, normal cells and proteins in the environment surrounding the cancer makes finding new therapies difficult.
Our project will investigate how a protein called FGF2 influences different types of glioblastoma cells within a given tumour. We are researching the way in which FGF2 affects these different types of glioblastoma cells in different ways, with some becoming more aggressive in direct response to FGF2. We propose that FGF2 does this by attaching to different types of receptors on the surface of the different cell types. We will investigate how each cancer cell type can be distinguished by the specific receptors they have on their surface, and also which receptors cause the most severe responses and how these are distributed within any given tumour. By understanding the function of FGF2 and its receptors, we can get a better understanding of the aggressive nature of glioblastoma and use this to help with the development of new treatments. This will help us to focus more targeted drugs at these specific receptors, and also importantly, provides a means of predicting which patients would benefit most from this therapy.

This project will examine the contributions of fibroblast growth factor 2 (FGF2) signalling to tumour progression in glioblastoma, the most common brain cancer in adults. Glioblastoma has a median survival of only 15 months, and is characterized by diffuse infiltration of the healthy parenchyma, and resistance to therapies, which causes recurrence. The presence of FGF2 in the tumour microenvironment, its correlation with tumour grade in astrocytoma, and functions in self-renewal of brain cancer stem cells, support the notion that FGF2 contributes to malignancy and tumour progression in glioblastoma. But the precise actions of FGF2 remain unclear because the expression and functions of different FGF receptors on glioblastoma cells have not yet been investigated in a comprehensive manner. This fundamental lack of understanding limits the potential of therapies and diagnostics based on FGF2 signalling. Here, we hypothesise that FGF2 acts on different cell populations in glioblastoma (through different FGF receptors expressed on their surface) to promote both cancer stem-like cell self-renewal and tumour growth. We will unravel the cell-type specific expression patterns of FGFRs, and use these to isolate stem-like and non-stem glioblastoma cell populations. Genetic ablation and pharmacological blocking of FGFRs will provide proof-of-concept that targeting specific FGFRs may be therapeutically beneficial. Preliminary data suggests that this may enable development of more tumour-selective therapeutics. Transcriptional profiling will facilitate investigating how expression signatures of these cell populations contribute to intertumoural and intratumoural heterogeneity, and whether these can be used to identify biomarkers and/or methylation-based classifiers to improve patient selection for clinical trials.

Brain cancer affects almost 10.000 patients/year in the UK. The most frequent of these cancers in adults is glioblastoma, for which no known cure exists. More importantly, therapeutic advances have been very slow over the past 50 years, and have improved survival only marginally. The median survival with standard-of-care treatment is only 15 months, and thus, glioblastoma accounts for approximately 3% of all cancer-related deaths. There is an urgent need for new and more effective therapeutics.
It is anticipated that this project will impact on various scientific and clinical levels. Firstly, the proposed study will refine targets for glioma therapy on the cellular and molecular level. There are currently two FGFR inhibitor in phase I/II clinical trials, but these inhibitors are non-selective for FGFR1/2/3. Identification of tumour-specific (and potentially sub-population- and/or subclass-specific) FGFR targets will enable development of bespoke subtype-specific compounds with greater efficacy and reduced potential for off-target effects. FGF2 signalling is mainly neuroprotective in the naïve brain, reinforcing the need to develop FGFR-targeting therapies with limited potential for off-target effects.
Secondly, this project will increase the biological understanding (see academic beneficiaries) of tumour heterogeneity, and how molecular interactions and networks contribute to inter- and intra-tumoural heterogeneity. Furthermore, we will clarify how FGFR signalling networks may drive (or be driven by) glioblastoma molecular signatures. This is important because distinct cellular populations (as identified by their FGFR profiles) will have different therapeutic resistance characteristics, and data/models to improve our understanding of the cellular heterogeneity in glioblastoma will help selecting correct/more effective targeted treatments and patient selection for future clinical trials.
Thirdly, FGF2 is widely used among researchers investigating brain cancer who employ sphere cultures and/or stem cell paradigms. To date, the specific actions and cellular targets of FGF2 in these models are incompletely understood. This project will reveal the functions of FGF2 in glioblastoma, and thus help improve in vitro models of brain cancer for better drug development.
Finally, FGF/FGFR signalling is also relevant in other cancers, including bladder, breast and gastric cancer. Hence, identified targets in this study may prove beneficial for these cancers as well.