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Radiation-induced senescence in the brain microenvironment: Implications for glioblastoma recurrence and therapy

辐射诱导的大脑微环境衰老：对胶质母细胞瘤复发和治疗的影响

基本信息

批准号：
10211559
负责人：
Sandeep Burma
金额：
$ 36.81万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
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：
2021-04-16 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10211559
关键词：
Adjuvant Chemotherapy Astrocytes Brain Brain Glioblastoma Brain Neoplasms Cell Aging Cells DNA Repair DNA Sequence Alteration Development Glioblastoma Glioma Growth Growth Factor Human Ionizing radiation Lead Ligands Malignant neoplasm of brain Modality Modeling Mutation Patients Pharmaceutical Preparations Phenotype Publishing Radiation Radiation exposure Radiation therapy Radiosensitization Recurrence Recurrent tumor Refractory Research Resistance Specimen Testing Therapeutic Therapeutic Intervention Transgenic Mice brain cell cancer stem cell efficacy testing genetic signature improved improved outcome mouse model neoplastic cell novel novel strategies patient derived xenograft model pre-clinical radiation resistance radioresistant resistance mechanism senescence temozolomide therapeutically effective therapy resistant transcription factor transcriptional reprogramming translational approach tumor tumorigenic

项目摘要

Abstract Glioblastomas (GBM) are aggressive and radioresistant brain cancers for which better therapeutic approaches are desperately needed. GBM patients are treated with 50-60 Gy of ionizing radiation (IR), and concurrent and adjuvant chemotherapy with temozolomide (TMZ). Radiation still remains the most effective therapeutic modality for GBM, yet these tumors inevitably recur, and the recurrent tumors are highly resistant to standard therapy. Any improvement in therapy would require a better understanding of the basis of GBM recurrence and therapy resistance of the recurrent tumor. Published research from our lab with transgenic mouse models has established that IR is potently gliomagenic, and that gliomas arising after radiation exposure are marked by genomic alterations such as MET amplification which promote a cancer stem cell phenotype and radioresistance. This raises the possibility that genetic alterations in GBM cells wrought by radiation therapy could render the recurrent tumor refractory to further therapeutic intervention. Exciting new results from our lab show that radiation also promotes the development of a senescence-associated secretory phenotype (SASP) in the brain microenvironment which promotes tumor development via secretion of growth factors like HGF (ligand for MET). This suggests that radiation-induced senescence of normal brain cells in the vicinity of the tumor could alter the microenvironment to promote tumor recurrence and radioresistance. Translationally significant results from our lab show that novel “senolytic” drugs can selectively eliminate senescent astrocytes in the brain and mitigate the pro-tumorigenic effects of SASP. We hypothesize that radiotherapy-induced genetic alterations in GBM cells (e.g., MET amplification) cooperate with senescence-associated changes in the brain microenvironment (e.g., HGF secretion) to promote tumor recurrence and radioresistance. We propose to analyze if “senolytics” can selectively kill senescent brain cells arising due to radiotherapy, thereby radiosensitizing GBM and delaying tumor recurrence. There is an urgent need for experimental strategies to understand such “acquired” therapy-resistance mechanisms in GBM and develop translational approaches. We have developed novel patient-derived xenograft (PDX) and syngeneic models of GBM recurrence for this purpose. Using these models, and human GBM specimens, we will investigate (1) how MET amplification caused by radiotherapy might, via reprogramming transcription factors like SOX2 and OLIG2, generate cancer stem cells with augmented DNA repair capabilities, (2) how secretion of tumor promoting factors, like the MET ligand HGF, by senescent astrocytes might promote growth and radioresistance of GBM cells with MET amplification, and (3) how cooperation between the GBM and its senescent microenvironment can be negated with “senolytic” drugs in order to improve the outcome of GBM therapy. This project can lead to the development of effective strategies to treat GBM that take into consideration both changes to the GBM cell and the brain microenvironment during radiotherapy.

抽象的胶质母细胞瘤 (GBM) 是一种侵袭性且抗辐射的脑癌，有更好的治疗方法是迫切需要的。 GBM 患者接受 50-60 Gy 的电离辐射 (IR) 治疗，同时进行替莫唑胺（TMZ）辅助化疗。放射仍然是最有效的治疗方法 GBM 的治疗方式，但这些肿瘤不可避免地会复发，并且复发的肿瘤对标准具有高度耐药性治疗。治疗的任何改进都需要更好地了解 GBM 复发的基础和复发肿瘤的治疗耐药性。我们实验室发表的转基因小鼠模型研究确定 IR 具有潜在的神经胶质瘤发生作用，并且辐射暴露后出现的神经胶质瘤的特征是基因组改变，例如促进癌症干细胞表型的 MET 扩增，辐射抗性。这提出了放疗引起 GBM 细胞基因改变的可能性可能会使复发性肿瘤难以进一步治疗干预。我们实验室的令人兴奋的新结果表明辐射还促进衰老相关分泌表型（SASP）的发展大脑微环境中通过分泌 HGF 等生长因子促进肿瘤发展（MET 的配体）。这表明辐射诱导了大脑周围正常脑细胞的衰老。肿瘤可能改变微环境，促进肿瘤复发和放射抵抗。平移地我们实验室的重要结果表明，新型“senolytic”药物可以选择性地消除衰老的星形胶质细胞并减轻 SASP 的促肿瘤作用。我们假设放射治疗引起的 GBM 细胞的遗传改变（例如 MET 扩增）与衰老相关脑微环境的变化（例如 HGF 分泌）促进肿瘤复发和辐射抗性。我们建议分析“senolytics”是否可以选择性杀死出现的衰老脑细胞由于放射治疗，从而使 GBM 放射增敏并延迟肿瘤复发。有紧急情况需要实验策略来了解 GBM 中的这种“获得性”治疗抵抗机制开发转化方法。我们开发了新型患者来源的异种移植物（PDX）和同基因移植物为此目的建立 GBM 复发模型。使用这些模型和人类 GBM 标本，我们将研究 (1) 放疗引起的 MET 扩增如何通过重编程转录因子来进行像 SOX2 和 OLIG2 一样，产生具有增强 DNA 修复能力的癌症干细胞，(2) 如何分泌衰老星形胶质细胞产生的肿瘤促进因子（如 MET 配体 HGF）可能会促进生长和 MET 扩增的 GBM 细胞的放射抗性，以及（3）GBM 及其之间如何合作可以用“衰老”药物消除衰老微环境，以改善 GBM 的治疗结果治疗。该项目可以制定有效的策略来治疗 GBM，其中考虑到考虑放疗期间 GBM 细胞和大脑微环境的变化。