Radiation-induced vascular reprogramming in glioblastoma

放射诱导的胶质母细胞瘤血管重编程

• 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
• 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

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 胶质母细胞瘤（GBM），最常见的原发性脑肿瘤几乎总是致命的。的主要模式 手术、放疗和替莫唑胺化疗等治疗仅使 生存GBM的一个标志是它们的高血管分布。GBM内的血管，主要由 内皮细胞和周细胞不仅为肿瘤提供营养和氧气， 而且还为肿瘤细胞提供直接的营养支持，并作为迁移出肿瘤的管道。 然而，针对肿瘤血管系统的抗血管生成疗法尚未成功。一些 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， 尽管肿瘤衍生的内皮细胞在未治疗的肿瘤中相对罕见。的数量 肿瘤衍生的内皮细胞在复发肿瘤中大大增加，这表明胶质瘤治疗， 像辐射一样，会影响这个过程。我们的初步研究表明，辐射可以诱导 在体外和动物模型体内产生内皮样和周细胞样细胞。这些重新编程的 细胞对于体内放射后肿瘤的生长是重要的，我们已经开始确定 重编程的血管细胞产生的因子，以支持剩余肿瘤细胞的生长， 辐射我们的初步数据表明，辐射会诱导染色质状态改变，从而允许 重编程发生;一个过程，这是潜在的治疗靶向通过抑制的 组蛋白乙酰转移酶（HAT），P300。当前研究的目标是了解 血管重编程（RIR），并确定它如何影响脑肿瘤生物学。我们的假设是 血管重编程细胞在严酷的环境下为剩余的肿瘤细胞提供关键的营养支持。 辐射后出现的症状。首先，在目标1中，我们将确定是否与治疗相关 放射剂量促进血管RIR。然后，我们将使用细胞消融策略来验证我们的初步研究。 数据表明辐射诱导的重编程对肿瘤的后续生长很重要 放射治疗后使用异种移植和免疫活性同基因小鼠模型。 接下来，我们将探讨辐射重编程内皮样细胞和周细胞样细胞的机制 促进剩余肿瘤的生长，确定它们阐述了哪些特定因素，以及是否 这些因子是放射后肿瘤存活和生长的原因。然后我们将检验这个假设 辐射通过改变染色质可及性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，允许进入 血管特异性转录因子。最后，我们将使用药物治疗靶点， 通过抑制P300 HAT的RIR过程。这些实验可能会导致对 研究放射治疗抵抗的潜在机制，并为新的治疗方法打开大门。