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：
10540761
负责人：
HARLEY IAN KORNBLUM
金额：
$ 46.41万
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/10540761
关键词：
Ablation Angiogenesis Inhibitors Animal Experiments Animal Model 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 Mediating Modeling Molecular Nutrient Operative Surgical Procedures Oxygen Pericytes Pharmaceutical Preparations 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 Therapeutically Targetable Tumor Biology Tumor Promotion Tumor-Derived Xenograft Model Xenograft procedure bevacizumab candidate validation chromatin modification clinically relevant experimental study histone acetyltransferase histone modification improved in vivo in vivo Model loss of function migration mouse model neoplastic cell novel therapeutics pharmacologic 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.

概括胶质母细胞瘤（GBM）是最常见的原发性脑肿瘤，几乎总是致命的。治疗——手术、放疗和替莫唑胺化疗——仅带来了微小的改善 GBM 的一个标志是 GBM 内的血管丰富，主要由血管组成。内皮细胞和周细胞，不仅发挥着为肿瘤提供营养和氧气的重要作用，而且还为肿瘤细胞提供直接的营养支持，并充当肿瘤细胞迁移出肿瘤的通道。然而，针对肿瘤脉管系统的抗血管生成疗法尚未取得成功。研究表明肿瘤周细胞和内皮细胞可以直接来源于肿瘤细胞，尽管肿瘤源性内皮细胞在未经治疗的肿瘤中相对罕见。肿瘤来源的内皮细胞在复发性肿瘤中大大增加，表明神经胶质瘤治疗，例如我们的初步研究表明，辐射可以诱发这一过程。在体外和体内动物模型中产生内皮样和周细胞样细胞。细胞对于体内辐射后肿瘤的生长很重要，我们已经开始定义什么重新编程的血管细胞产生的因子支持剩余肿瘤细胞的生长我们的初步数据表明，辐射会诱导染色质状态，从而允许重编程的发生；通过抑制组蛋白乙酰转移酶（HAT），P300 当前研究的目标是了解这一过程。血管重编程（RIR）并确定它如何影响脑肿瘤生物学。血管重编程细胞为严酷环境下剩余的肿瘤细胞提供关键的营养支持首先，在目标 1 中，我们将确定是否具有治疗相关性。然后，我们将使用细胞消融策略来验证我们的初步结果。数据表明辐射诱导的重编程对于肿瘤的后续生长很重要使用异种移植和免疫活性同基因小鼠模型进行放射治疗后。接下来，我们将探讨辐射重编程内皮样和周细胞样细胞的机制促进剩余肿瘤的生长，确定它们阐述的具体因素，以及是否这些因素导致辐射后肿瘤的存活和生长，然后我们将检验该假设。辐射通过改变染色质可及性来诱导血管样细胞的形成通过 P300 组蛋白乙酰转移酶增强组蛋白乙酰化，从而允许访问最后，我们将使用药物来靶向治疗。通过抑制 P300 HAT 的 RIR 过程可以使人们对 RIR 过程有新的认识。放射治疗耐药性的潜在机制，并为新疗法打开了大门。