Mouse Models in Preclinical Drug Development: Applications to CNS Models

Abstract

Primary tumors of the CNS can be divided into several groups; the most common in adults being the gliomas and in children the medulloblastomas (Kleihues et al. J Neuropathol Exp Neurol 61(3):215–225, 2002). Gliomas are thought to arise from cells at some point of differentiation along glial lineage leading to astrocytes and oligodendrocytes. In the normal brain, the primary function of astrocytes is to maintain homeostasis of neuronal extracellular milieu and protect the neurons by establishing the blood–brain barrier during development. Oligodendrocytes provide the CNS axons with myelin sheaths that insulate the neurons and thereby accelerating the action potential transduction. By contrast, medulloblastomas appear to arise from cells of the external granule layer in the developing cerebellum that give rise to the internal granule layer neurons. These tumors are the most common tumor found in children. Gliomas are relatively radiation-resistant and the clinical outcome for patients with the most aggressive and common of the gliomas, Glioblastoma Multiforme or GBM, has been poor and essentially unchanged in the last 50 years with the median survival averaging 12–14 months (CBTRUS. Statistical report: primary brain tumors in the USA). Medulloblastomas on the other hand are much more responsive than GBMs to radiation and chemotherapy with a 70% cure rate. An important step toward improving existing treatments and discovering new ones comes from creating genetically and histologically accurate mouse models that can be used as a representative system of human tumors in order to study the biological and mechanistic causes of brain cancer and the way that these tumor interact with their microenvironment. Furthermore, accurate mouse models of these tumors are helping us to identify novel targets and therapies for clinical testing (Hambardzumyan et al. Expert Opin 2(11):1435–1451, 2007).