Molecular Therapies for Malignant Glioma

Due to the dismal prognosis of malignant glioma with currently available therapies there is an urgent need for new treatments based on a better molecular understanding of gliomagenesis. Several concepts of molecular therapies for malignant glioma are currently being studied in preclinical and clinical settings, including small molecules targeting specific receptor-mediated signaling pathways and gene therapy. Many growth factors, growth factor receptors--usually receptor tyrosine kinases--and receptor-associated signaling pathways are critically involved in gliomagenesis. Numerous selective inhibitors, which specifically block such molecules, are currently evaluated for clinical applicability. Several gene therapy approaches have shown antitumor efficacy in experimental studies, and the first clinical trials for the treatment of malignant glioma were conducted in the 1990s. In clinical trials, retroviral herpes-simplex-thymidinkinase- (HSV-Tk-) gene therapy has been the pioneering and most commonly used approach. However, efficient gene delivery into the tumor cells still remains the crucial obstacle for successful clinical gene therapy. During the past few years a number of new gene transfer vectors based on adeno-, adeno-associated-, herpes- and lentiviruses as well as new carrier cell systems, including neural and endothelial progenitor cells, have been developed. In addition, antisense technologies have advanced in recent years and entered clinical testing utilizing intratumoral administration by convection-enhanced delivery, exemplified by ongoing clinical trials of intratumoral administration of antisense TGF-beta. This paper summarizes some of these recent developments in molecular therapies for malignant glioma, focusing on targeted therapies using selective small molecules and gene therapy concepts.