Jesper Dupont Ewald

Neurotrophic factor-mediated chemoresistance in glioblastoma

Background

Glioblastoma, the most prevalent primary malignant brain tumor, has a poor prognosis with a median survival of 14 months. In fact - brain cancer patients are those patients having the shortest life expectancy after diagnosis - compared to all cancers patients. A major therapeutic problem is chemoresistance. Our research group has novel data showing that treatment of patient-derived glioblastoma cells with the type of chemotherapy given to the patients leads to pronounced upregulation of glial-cell-line-derived neurotrophic factor (GDNF), potentially protecting the glioblastoma cells against chemotherapy. GDNF is a potent factor in the brain - supporting growth, but its role in therapy resistance in glioblastomas is unknown.

Aim

The aim of my PhD project is to interrogate, whether GDNF upregulation is a clinically relevant resistance mechanism in glioblastomas.

Methods

First - I will investigate how active the resistance mechanism is in different tumors using a series of patient-derived glioblastoma cultures from ten different patients. I will measure GDNF levels and levels of a set of other molecules that potentially interact with GDNF and play a role for the resistance mechanism. Next - I will investigate the potential role of the microenvironment around the tumor cells. Other cell types like inflammatory cells around the tumor cells may play a role and support the resistance mechanism. I will also investigate whether tumor cells being most likely cancer stem cells are likely to use the resistance mechanism to survive chemotherapy. Cancer stem cells are most likely the type of cells that initiate the cancer disease. An important part of the project will be to identify the molecular mechanisms responsible for the resistance mechanism and to test potential novel therapeutic strategies. I will do this by in vitro (cell culture) experiments and by mice experiments. Our research group has developed a preclinical model, where mice develop patient-like brain tumors after implantation of patient-derived glioblastoma cells to their brains.

Feasibility and collaboration

I will carry out this project within an experienced brain cancer research group and together with experts in neurobiology and experts in glioblastoma and stem cell biology from Cleveland, USA. I have one year of experience in working in laboratories with cancer cell cultures and performing mouse model experiments so many of the methods are well known for me. In addition I´m supported by a molecular biologist and a new postdoc in our group, who is very experienced in the area of molecular techniques and I will have a 6 month stay in Cleveland, USA in the challenging molecular part of the project.

Impact

This work will lay the foundation for the development of GDNF-targeted therapies to increase the vulnerability of glioblastomas to standard therapeutic paradigms with chemotherapy. It is of major importance that the project is based on patient-derived cancer tissue. Part of our strategy is to test drugs already being in clinical trial for other purposes. Successful testing of these drugs will make us able to move very quickly to clinical trial. Therapies targeting growth factor receptors have in fact been successful in e.g. breast and lung cancer. In a related project, our research group has filed a patent application with results justifying a clinical brain cancer trial. The work towards this potential trial is ongoing. This emphasizes the strong translational and clinical focus of our research group and of the current project.