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 Glioublastomas（GBM）是侵略性和放射耐药性脑癌迫切需要GBM的患者进行50-60 Gy的电离辐射（IR），并并发替莫唑胺（TMZ）的辅助化疗。 GBM的模态，但这些肿瘤不可避免地可侵蚀，并且肿瘤对标准具有抗性治疗的任何改善都需要更好地理解GBM复发的基础复发性肿瘤的治疗耐药性。确定IR是有效的神经胶质素，并且在放射性暴露后产生的神经胶质瘤标志着基因组改变，例如MET扩增，促进癌症干细胞表型和放射线抗性。可以使难治性进一步治疗干预。表明辐射还促进了鼻骨 - 以下分泌表型（SASP）的发展在大脑微环境中，通过分泌HGF等生长因素促进肿瘤的发展（Met的配体）。肿瘤政变改变了微环境，以促进肿瘤复发和放射线我们实验室的重大结果表明，新型的“鼻溶剂”药物可以选择以叶片为主的星形胶质细胞在大脑中，我们假设放射疗法诱导的SASP促肿瘤效应。 GBM细胞中的遗传改变（例如，MED扩增）与衰老相关的合作大脑微环境的变化（例如，HGF分泌）促进肿瘤复发，辐射率。由于放射疗法，因此放射敏感的GBM并延迟了肿瘤复发。需要实验策略，以了解GBM和和和开发翻译方法。使用这些模型的GBM复发的模型和人类GBM标本研究（1）通过重编程转录因子，放射疗法引起的MET扩增如何像Sox2和Olig2一样，具有增强DNA修复能力的癌症干细胞，（2）分泌如何衰老的星形胶质细胞的肿瘤促进因素，例如Met配体HGF，可能会促进生长和 GBM细胞具有MET扩增的放射性，（3）GBM与ITS之间的合作如何衰老的微环境可以用“鼻孔”药物否定，以改善GBM的结果疗法。在放射疗法期间，GBM细胞和脑微环境的考虑都会改变。