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Radiation-induced vascular reprogramming in glioblastoma

放射诱导的胶质母细胞瘤血管重编程

基本信息

批准号：
10375792
负责人：
HARLEY IAN KORNBLUM
金额：
$ 49.21万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-15 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10375792
关键词：
Ablation Animal Model Animals Blood Vessels Brain Neoplasms Cells Chemotherapy and/or radiation Chromatin Data EP300 gene Endothelial Cells Endothelium Glioblastoma Glioma Goals Growth Histone Acetylation Human Immune system Immunocompetent In Vitro Lead Mediating Modeling Molecular Nutrient Operative Surgical Procedures Out-Migrations Oxygen Pericytes Pharmaceutical Preparations Pharmacology Play Primary Brain Neoplasms Process Production Radiation Radiation Dose Unit Radiation therapy Radiobiology Recurrence Recurrent tumor Resistance Role Specific qualifier value Supporting Cell Testing Therapeutic Tumor Biology Tumor-Derived Xenograft Model Xenograft procedure bevacizumab chromatin modification clinically relevant experimental study histone modification in vivo in vivo Model loss of function mouse model neoplastic cell novel therapeutics radiation effect temozolomide therapeutic target therapy resistant transcription factor tumor tumor growth virtual

项目摘要

Summary Glioblastoma (GBM), the most common primary brain tumor is virtually always fatal. The primary modes of therapy—surgery, radiation and chemotherapy with temozolomide—have led to only marginal improvements in survival. A hallmark of GBM is their high vascularity. Blood vessels within GBM, consisting of mostly endothelial cells and pericytes, not only play the important role of providing nutrients and oxygen to the tumor, but also provide direct trophic support to the tumor cells and serve as conduits for migration out of the tumor. However, anti-angiogenic therapies directed against tumor vasculature have not been successful. A number of studies have revealed that tumor pericytes and endothelial cells can be derived directly from tumor cells, although tumor-derived endothelial cells are relatively rare occurrences in untreated tumors. The number of tumor-derived endothelial cells is greatly increased in recurrent tumors, suggesting that glioma therapy, such as radiation, could influence this process. Our preliminary studies show that radiation can induce the production of endothelial-like and pericyte-like cells in vitro and in animal models in vivo. These reprogrammed cells are important for the growth of the tumor following radiation in vivo and we have begun to define what factors the reprogrammed vascular cells produce to support the growth of the remaining tumor cells following radiation. Our preliminary data indicate that radiation induces altered chromatin states that allow for reprogramming to occur; a process that is potentially therapeutically targetable through the inhibition of the histone acetyltransferase (HAT), P300. The goals of the current studies are to understand the process of vascular reprogramming (RIR) and to determine how it influences brain tumor biology. Our hypothesis is that vascular reprogrammed cells provide critical trophic support to the remaining tumor cells under the harsh conditions that occur following radiation. First, in Aim 1 we will determine whether therapeutically relevant doses of radiation promote vascular RIR. We will then use cell ablation strategies to validate our preliminary data indicating that radiation-induced reprogramming is important for the subsequent growth of the tumor following radiation treatment using both xenotransplantation and immunocompetent syngeneic mouse models. Next, we will explore the mechanisms by which radiation reprogrammed endothelial-like and pericyte-like cells promote the growth of the remaining tumor, determining what specific factors they elaborate, and whether these factors are responsible for tumor survival and growth following radiation. We will then test the hypothesis that radiation induces the formation of vascular-like cells through modification of chromatin accessibility via augmentation of histone acetylation through the P300 histone acetyltransferase, allowing for access of vascular-specifying transcription factors. Finally, we will use pharmacologic agents to therapeutically target the process of RIR through inhibition of the P300 HAT. These experiments can lead to a new understanding of mechanisms underlying resistance to radiation therapy and open the door to new treatments.

总结