Glioblastomas (GBMs), the most common and malignant of all primary brain tumors, infiltrate the brain and are lethal. GBM can be diagnosed de novo, or result from progression of lower-grade gliomas. All GBMs undergo the same non-curative treatment, including surgery, chemotherapy and radiation. Given that molecular characteristics are highly variable across GBMs, these tumors have been classified into subtypes based on gene expression patterns. These expression patterns and their underlying mechanisms might provide a unique tumoral vulnerability, a possibility not yet explored. Many transcription factors that control gene expression on proneural GBM subtype during glioma progression appear to be modulated by Topoisomerase IIA (TOP2A), an enzyme expressed by these tumors since early stages. TOP2A is involved in cell cycle progression, DNA repair and transcription. TOP2A de-coils DNA and enhances chromatin accessibility by creating transient double strand-DNA breaks (DSB). In stem cells, TOP2A regulates transcription at loci with histone 3 lysine 4 methylation (H3K4me2), but its role in GBM is unknown. Etoposide, a TOP2A-targeting drug that induces cytotoxic DSB is efficacious for a subset of GBM patients. Using mouse models, I showed that delivery of etoposide directly into these brain tumors led to higher efficacy than the concentration achievable by systemic delivery. However, differences in etoposide sensitivity across GBMs remain unexplained. I propose to study TOP2A's role on transcriptional regulation on GBM, and how it relates to etoposide sensitivity. To do this, using cell lines I will investigate whether histone methylation mark H3K4me2 influences TOP2A binding to the tumor genome, and how this affects gene expression. Using human GBM specimens, I will compare samples with elevated TOP2A to those lacking this enzyme. I will also explore TOP2A activity across different tumor grades. Using neuro-navigation guidance, I will investigate the differences in TOP2A at the resectable portion of GBM, and at the tumor margins to explore whether tumor cells infiltrating the brain can be targeted with etoposide. TOP2A DNA binding and DSB are common to transcriptional regulation by this enzyme and its targeting with etoposide, potentially rendering tumors that are transcriptionally regulated by TOP2A susceptible to this drug. I will explore this relationship on GBM cell lines with variable etoposide sensitivity. To explore the role of TOP2A on progression, I will study TOP2A transcriptional regulation at different times in transgenic mouse gliomas. To explore the transcriptional alterations caused by etoposide in gliomas, I will study tumors following 12 hours of etoposide treatment, and at recurrence. In summary, I propose to characterize transcriptional regulation by TOP2A in GBM and its role on progression. I will identify the molecular criteria for personalizing intratumoral etoposide therapy and understand how disruption of transcriptional regulation with etoposide influences recurrence. TOP2A as a target for infiltrating tumor also will be explored. The overarching goal is to design a personalized intratumoral etoposide trial for GBMs.
This application aims to study the role of Topoisomerase IIA (TOP2A) in transcriptional regulation in glioblastomas, and explore its therapeutic targeting using intratumoral etoposide for this lethal form of brain cancer. I hypothesize that TOP2A plays a vital role regulating gene expression in a subset of glioblastomas. I will determine which subset of these tumors is regulated by TOP2A, which will provide an insight into tumoral vulnerability to etoposide, a drug that targets TOP2A. This information can be used as criteria to select patients for a future clinical trial of intratumoral etoposide for glioblastoma.
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