Our research program is focused on molecular signaling pathways that regulate cell growth in the nervous system during embryonic development and tumorigenesis. Malignant gliomas are primary brain tumors that are recalcitrant to current therapies and patients with this disease currently have a poor prognosis. Malignant gliomas are composed of heterogeneous cell types and identification of particular cell types within the tumor that contribute to growth and recurrence may lead to the development of more effective therapies. In particular, the identification of tumor-initiating cells has provided a framework for conceptualizing a hierarchical arrangement of multipotent cancer stem cells giving rise to transit-amplifying and postmitotic glioma cell types. Impediments to investigating this fundamental concept in glioma biology include the lack of cell markers for characterizing the phenotypes, lineage relationships and regulatory molecular pathways of these putative cellular compartments.
One avenue for investigating brain tumor heterogeneity in our laboratory includes studies on the Hedgehog signaling pathway. Towards these goals, the laboratory utilizes a patient tissue repository to identify the specific subtypes of malignant gliomas in which the Hedgehog signaling pathway is operational and activated. Our research team has established a preclinical model for growing human malignant gliomas in mice to demonstrate that Hedgehog signaling regulates glioma growth and that pathway inhibition enhances survival. The Hedgehog pathway appears to be activated in a subpopulation of glioma cells, and determining how Hedgehog signaling impacts this cellular compartment in gliomas is a primary focus of research. Longer term goals of these preclinical studies are to design clinical trials of Hedgehog inhibitors based upon selecting patients with malignant glioma who might best respond to Hedgehog inhibitors, defining the mechanism of action of Hedgehog pathway inhibition on glioma cancer stem cells and avoiding potential mechanisms of drug resistance. Our laboratory is also involved in several collaborative efforts to model glioma cellular compartments. One of these is to generate monoclonal antibodies against heterogeneous malignant glioma cell types. A central goal of these studies is to determine if these antibodies can be used to define subclasses of glioma tumor initiating cells and their lineages.