Author:

Abstract:

Multi-modal small animal imaging for brain tumor therapy assessment Malignant gliomas are the most common tumors arising in the central nervous system. Despite advances in neurosurgery and adjuvant radio - and chemotherapy, these patients however still face a dismal prognosis. A major reason for their bad prognosis is the infiltrative growth pattern of these tumors, with single tumor cells migrating distantly fromthe solid tumor mass and infiltrating normal brain tissue, where they can cause recurrent tumors. One promising therapeutic approach for gliomais the delivery of therapeutic agents by engrafted cells that have the capacity to specifically migrate to pathogenic foci and in particular totrack infiltrating tumor cells. In so called bystander mediated killingapproaches, therapeutic cells produce enzymes that are responsible for the cell death of tumor cells (for example thymidine kinase (TK) expressing cells). The approach of using stem cells as suitable cellular vehicles for glioma therapy relies however on assumptions of the migration potential and biodistribution of these cells. These therapies often lack knowledge based administration of required pro – drugs and therefore knowledge based initiation of therapy. This promising method can be optimizedby labelling therapeutic cells in vitro with an MRI contrast agent, followed by non - invasive monitoring of their tumor infiltration using MR imaging after implantation and administration of the pro - drug at the appropriate time point. In this study, stem cells willbe labelled using non - toxic, superparamagnetic nano -particles as MRIcontrast agent. Once the cells are labelled with nanoparticles and transduced with lentiviral vectors containing the HSV-TK and a fluorescent protein, the cells will be implanted in the rat and / or mouse brain. Thetherapeutic effect will be achieved by expression of suicide genes and bystander - mediated glioma cell killing. The thymidine kinase of human cells, unlike that of the herpes simplex virus, is unable to transform the pro – drug gancyclovir into its toxic derivative. This transformationthus results in a product, which is only toxic for the implanted stem cells. A process called bystander mediated cell killing, which involves gap junction formation, ensures that also tumor cells adjacent to these stem cells are destroyed. To achieve a maximal therapeutic effect though,the pro – drug has to be delivered at the time of completed migration of the stem cells to the pathogenic focus and in particular to infiltrating tumor cells to avoid tumor reoccurrence. MRI will be used to determine the optimal time for pro – drug administration, while the effect of therapy will be followed up by optical and PET imaging. This project will thus aim to overcome remaining shortcomings of apromising therapy approach by combining the highly successful bystanderkilling effect of stem cells with the non – invasive guidanceof the pro – drug administration.