Molecular Mechanisms and Therapeutic Approaches to Malignant Gliomas

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 DESCRIPTION (provided by applicant): Over 22,500 Americans will be diagnosed with brain tumors, and most of them will succumb to the disease. Our laboratory has discovered that gliomas originate by reprogramming of terminally differentiated astrocytes, neurons, and neural stem cells (NSCs) following oncogenic insult. This observation will explain why even after very successful surgery, where the surgeon has removed the majority of the cancer tissue, the tumors recur frequently. Additionally the tumors can transdifferentiate into functional blood vessels, thus thwarting the traditional anti-angiogenic therapies. The Verma laboratory seeks to understand the molecular mechanisms of dedifferentiation, trans-differentiation, and will undertake possible therapeutic approaches. Aim 1: Phenocopying human glioblastoma multiforme (GBM) in a mouse model for therapeutic treatment. The Verma laboratory plans to phenocopy the radiotherapy and chemotherapy (temozolomide) treatments that patients undergo following GBM diagnosis in our lentiviral induced GBM system. The aim is to mimic this situation and evaluate the effect of these treatments on tumor growth and invasion. Aim 2: Mechanisms of tumor cell trans-differentiation to endothelial cells: Trans-differentiation of gliom cells to endothelial cells (TDECs) was a major surprise and reflects the plasticity of tumor cells. To understand molecular mechanisms involved in their formation and delineation of their specific characteristics, detailed genetic profiling of mouse and human TDECs will be carried out. Specifically the role of Sema3e and HIF-1 in tumor development and TDEC formation will be determined. Aim 3: Novel therapeutic approaches for GBM Treatment: Since the GBM mouse models generally recapitulate the pathologic and molecular hallmarks of the human disease, the Verma laboratory proposes to take advantage of the preclinical mouse GBM model to test novel therapeutic approaches targeting: (a) angiogenesis including TDEC angiogenesis, and anti-angiogenic therapy-induced hyperinvasiveness, and (b) the NFkB pathway, which we have found to be constitutively activated in GBM tumors. This laboratory has generated a unique model of mouse gliomas that can serve as a preclinical model for a variety of mechanistic and therapeutic modalities being developed in the Verma laboratory.