David N. Louis, MD
Massachusetts General Hospital
Benjamin Castleman Professor of Pathology
Harvard Medical School
Our laboratory investigates the molecular genetic basis of human brain tumors. Brain tumors are the second most frequent malignancy of childhood and their incidence in adults increases with advancing age. These are also among the most devastating of human malignancies, affecting the organ that defines the "self," often severely compromising quality of life.
Malignant gliomas of the cerebral hemispheres in adults are the most common brain tumors, and are the focus of our laboratory efforts. Malignant gliomas are classified as astrocytomas, oligodendrogliomas, and oligoastrocytomas. The most aggressive, astrocytoma, is referred to as glioblastoma. Elucidating the molecular basis of glioma formation may impact both diagnostic and therapeutic aspects of clinical neuro-oncology.
Over the past twenty years, we have demonstrated alterations characteristic of specific glioma subtypes and grades. We originally demonstrated that molecular genetic analysis could be used to define clinicopathologically relevant subsets of glioblastomas: those with TP53 mutations and those with EGFR amplification. We later showed that molecular genetic alterations are powerful predictors of survival and therapeutic response in patients with anaplastic oligodendrogliomas and other oligodendrogliomas. These findings have already led to clinical applications, with testing performed worldwide.
We have also investigated whether gene expression profiling could be used to classify high grade gliomas in a manner more objective, explicit, and consistent than standard pathology, and suggested that class prediction models, based on defined molecular profiles, classify diagnostically challenging malignant gliomas in a manner that better correlates with clinical outcome than does standard pathology. Most recently, our laboratory has uncovered and elucidated a mechanism of resistance to standard alkylating agent chemotherapy of glioblastoma, demonstrating common inactivation of MSH6 in glioblastomas exposed to temozolamide. We are currently studying other means by which glioblastomas develop resistance to chemotherapeutic agents.
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