Neural Stem Cells to Induce Apoptosis in Glial Tumors

Children'S Hospital Boston, Boston MA

Investigators

Abstract

Despite recent advances in neurosurgery, radiotherapy, chemotherapy and gene therapy, prognosis for patients with malignant gliomas remains poor. There is grave need for novel approaches to the therapy of these tumors. Obstacles to treatment of gliomas include the diffuse infiltrating nature of glial tumor cells, and difficulties in administration of anti-neoplastic agents to the brain. Previous research in our laboratory has shown that human neural stem cells (NSC) have the unique ability to migrate in juxtaposition to infiltrating glioma cells when transplanted into murine brain tumor models. This tumor "tracking" behavior of NSC's makes them an ideal platform for the delivery of anti-neoplastic agents to infiltrating glioma cells. Past research has shown that glioma cells express the Fas receptor (FasR), and will undergo apoptosis when ligated to the Fas ligand (Fast). The expression of FasR increases with increasing malignancy of glial tumors. There is no FasR expression in normal brain tissue. We propose to deliver FasL to glial tumors to induce apoptosis by transplanting genetically engineered NSC's that express Fas ligand (FasL). FasL-expression will be achieved by transfection of NSC's with a retroviral contruct containing human FasL DNA. Normal brain is immune to FasL-mediated apoptosis as there is no expression of FasR on normal brain cells. The unique migratory behavior of NSC's in juxtaposition to tumor cells will allow delivery of FasL to infiltrating glial cells, potentially overcoming previous obstacles to the treatment of these tumors.