Characterization of mTOR signaling during early stages of gliomagenesis

Columbia University Health Sciences, New York NY

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Abstract

? DESCRIPTION (provided by applicant): Gliomas are the most common brain tumor for which conventional treatment has minimally improved survival rates. Gliomas are characterized by histology into a spectrum ranging from low to high grade tumors where low grade lesions can progress to high grade malignant tumors. Investigational treatment has been directed towards high grade gliomas but has been unsuccessful in treating this devastating disease. Investigating the early stages of glioma formation would enable the identification of mechanistic targets that prevent the progression from low to high grade glioma. PDGF is a growth factor that stimulates oligodendrocyte progenitor cell (OPC) proliferation via PDGFRa. mTOR signaling has been shown to mediate PDGF stimulated proliferation of OPCs. Overexpression of PDGFRa and upregulation of components of the mTOR pathway are frequent events in the proneural subtype of glioma. Deletion of p53 is also a frequent event in proneural gliomas, particularly during early stages of glioma formation. In addition to the canonical role of p53 in regulating transcription, p53 has been shown to inhibit mTOR signaling and regulate translation. We hypothesize that p53 deletion will render OPCs sensitive to mTOR inhibition both in vitro and in vivo. We will characterize the sensitivity to mTOR inhibition in the context of p53 deletion by assessing OPC cell survival and proliferation. Additionally, we aim to determine the role of mTOR signaling in OPC translation by ribosome profiling. To study the effects of mTOR inhibition in glioma progression, we will target mTOR signaling during early stages of glioma formation and assess tumor growth by histological analysis. This research will identify how p53 deletion contributes to alterations in gene expression at the level of translation via mTOR signaling and determine the effects of inhibiting mTOR signaling during early stages of glioma formation. Ultimately this will inform future studies of the molecular characteristics of the early stages of glioma formation which will guide the development of novel therapeutic targets that prevent glioma progression.