Targeting the Notch Pathway and the Role of the Tumor Microenvironment in Glioblastoma

Glioblastoma (GBM) is the most common primary adult brain tumor. The Notch pathway has been identified as deregulated in GBM, making it an attractive therapeutic target. Our studies demonstrate that Notch blockade using a gamma secretase inhibitor (GSI) is effective in significantly extending survival in vivo in mouse xenograft models. However, this result has not translated therapeutically into efficacy in human clinical trials. One potential explanation is the development of therapeutic resistance to Notch blockade. Our studies demonstrate it is possible to generate GSI resistant GBM cell lines, and that resistance is not mediated by reactivation of Notch blockade. Gene expression analyses suggest a potential role for the WNT pathway in driving GSI resistance. Animal models that more faithfully represent the human clinical settings are critical to drug development in GBM. The importance of the immune system in the tumor microenvironment has recently been appreciated, and the success of immune checkpoint inhibitors in extending survival in numerous cancers underscores its relevance. It is therefore important to develop mouse models with intact immune systems to facilitate drug development in the presence of an intact immune system. We describe an immune competent mouse xenograft model that recapitulates human GBM tumor growth more accurately than xenografts in immunodeficient mice