Description
Glioblastoma is the most common primary brain tumor in adults. A major problem preventing curative resection is the extensive infiltration of stem-like glioma cells into the central nervous system. The research proposed in the current project will lead to development of peptides that are capable of reaching infiltrative stem cell-like cells of glioblastoma. The peptides will be able to penetrate gliomas (and potentially other tumors) independent of their angiogenic status, and to deliver co-administered drugs to tumor propagating cells far from the bulk glioma lesion. The peptides will be coupled to therapeutic payloads to achieve selective elimination of the malignant cells for sustained therapeutic response. The project combines the expertise of the laboratory of Prof. Rolf Bjerkvig (the state of the art, clinically relevant human GBM models) and the laboratory of Dr Tambet Teesalu (targeted drug delivery technologies), to develop tumor penetrating peptides that target glioblastomas.
Summary of project results
Glioblastoma is the most common primary brain tumour in adults. Despite aggressive treatment, the majority of patients die within a year of diagnosis. A major problem preventing curative resection is the extensive infiltration of stem-like glioma cells in the brain. The goal of this innovative and highly risky project was to find the homing “courier” peptides for the precision-guided delivery of drugs and imaging agents to glioma cells. The researchers involved in the project transferred the glioma models from the University of Bergen to the University of Tartu and characterized the tumours with immunofluorescence staining, using cell type and status-specific antibodies and histochemistry. These advanced and clinically relevant glioma models from Bergen were used in Tartu to identify the peptides that home to glioma lesions and target infiltrative glioma stem-like cells. These new in vivo screens resulted in the identification of four candidate peptides with robust selectivity towards stem cell like glioma cells. In addition to peptides that target tumour cells, the screens resulted in the identification of a novel protumoral macrophage-targeting peptide. Also the ability of the peptides with regard to tumour selectivity and the activity of nanoparticle contrast agents was tested. These studies demonstrated that functionalisation with glioma homing peptides renders nanoparticles selective towards glioma lesions. This increase in tumour selectivity translated to improved tumour imaging and potentiated therapeutic response. The developed peptides are able to penetrate gliomas (and potentially other tumours) for precision-guided payload delivery. The preclinical data suggests that this strategy allows improved antitumor therapeutic response and warrants follow-up collaborative studies on optimising the platform for clinical development. The project also contributed significantly to three PhD projects that are expected to be completed later in 2017. Beyond immediate scientific and training outcomes, the project contributed to the bidirectional sharing of know-how between the partners and the establishment of long-lasting collaborative research activities and joint training programs between the laboratories in Bergen and Tartu.
Summary of bilateral results
The project combined Professor Rolf Bjerkvig’s (University of Bergen) laboratory’s expertise on the state-of-the-art, clinically relevant human glioblastoma models with the expertise of the laboratory of Dr. Tambet Teesalu (University of Tartu) on homing peptide screening platforms and targeted drug delivery technologies. This was an interdisciplinary collaboration that requires combination of complementary expertise available in Bjerkvig’s laboratory (tumor models and in vivo imaging of glioma) and in Teesalu’s laboratory (tumor homing peptide development, peptide chemistry, nanobiomedicine). The aims of the collaboration were not possible to achieve by either laboratories alone, and the partnership and complementarity of research profiles were critical for the success of the collaboration. The Norwegian partner can be regarded as outstanding partners in this project. They have provided for the Estonian group with an important complementary expertise on the highest quality level which was indispensable for the project and also will be in the future. This is one of the biggest achievements of the project. A big benefit of the current funding is the successful technology transfer from Bergen to Tartu, which will be extremely important for future activities of the Estonian researchers. The Norwegian partner was critical for establishing advanced clinically relevant glioma models in the Tartu laboratory. The quality of well characterized state of the art glioma models was a prerequisite for performing screens for clinical relevant glioma homing peptides. Specifically, Norwegian laboratory shared glioma models of different levels of “stemness” and other properties, that allowed Tartu laboratory to screen for and audit the new peptides in clincially relevant way. A main result of the interaction between the two laboratories has been the successful establishment of human derived glioblastoma xenograft models in Tartu and using the models to map tumor targeting peptides for precision-guided payload delivery. These xenograft models are not only based on the tumor models originally established in Bergen, but also on new models established in Estonia using know-how from Bjerkvig’s laboratory.