Challenges in the treatment of malignant glioma with oncolytic adenovirus

Sammanfattning: Malignant glioma is a tumor that spreads rapidly throughout brain and is almost impossible to remove completely by surgery. It is resistant to chemo- and radiotherapy and the prognosis is very poor. As a result, there is a desperate need for development of novel therapies against this devastating disease. Because of the heterogeneity in this cancer success has been limited, but a recent concept in cancer biology suggests that a small sub-population of cells within the tumor is responsible for initiation and maintenance of the whole tumor, the so-called cancer stem cells (CSC), a fact that could lead to new ways to treat cancer in the future. More specifically, a successful therapy has to target these CSC and in this way inhibit the re-growth of the tumor creating the possibilities for a more effective treatment against cancers such as malignant glioma. However, there is a lot of controversy surrounding this concept and in this thesis I have tried to clarify some of the uncertainties. Thus, since the CSC share many properties with normal neural stem cells (NSC) it could be that such a NCS gone awry is responsible for the CSC and the tumor. As a result, in my thesis, I have tried to look at cell surface markers for any similarities, or variations between the normal NSC and the CSC because this may give us an indication of the type of cells that are prone to transformation. In that case it would be easier to investigate which kind of changes lead to the development of a cancer cell. Additionally, in order to develop a new therapy against malignant glioma based on these possible findings we have chosen to use an adenovirus as a tool. Adenoviral infections are normally not dangerous to healthy individuals, and they are easy to manipulate so this makes them a good choice for cancer therapy. However, there is a common problem in viral treatment of cancer, which is one of the main reasons why treatments fail to give satisfactory results. This problem is the poor spread of the virus when injected into a tumor and I have as part of my work tried to identify mechanisms in order to solve it. Identifying such a mechanism can also answer some questions concerning the general problem in adenoviral biology, namely one of the reasons behind chronic adenoviral infections. We have discovered that during an adenovirus infection viral fiber proteins are secreted from the infected cell, which bind to and masks adjacent cells. Subsequently, because of this masking, as infected cells lyses and newly formed viral particles are released into the extra cellular space they infect new cells at a lower frequency. Identifying the type of cells where transformation takes place, and solving the problem of the poor spread of the virus when injected into a tumor, we hope to contribute to the development of new treatment regimes for malignant glioma in the future.