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:10394384
- 负责人:
- 金额:$ 34.94万
- 依托单位:
- 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:
- 关键词:Adjuvant ChemotherapyAstrocytesBrainBrain GlioblastomaBrain NeoplasmsCell AgingCellsDNA RepairDNA Sequence AlterationDevelopmentGlioblastomaGliomaGrowthGrowth FactorHumanIonizing radiationLeadLigandsMalignant neoplasm of brainModalityModelingMutationPatientsPharmaceutical PreparationsPhenotypePublishingRadiationRadiation exposureRadiation therapyRadiosensitizationRecurrenceRecurrent tumorRefractoryResearchResistanceSpecimenTestingTherapeuticTherapeutic InterventionTransgenic Micebrain cellcancer stem cellefficacy testinggenetic signatureimprovedimproved outcomemouse modelneoplastic cellnovelnovel strategiespatient derived xenograft modelpre-clinicalradiation resistanceradioresistantresistance mechanismsenescencetemozolomidetherapeutically effectivetherapy resistanttranscription factortranscriptional reprogrammingtranslational approachtumortumorigenic
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)是侵略性和放射性脑癌,以此更好地治疗方法
迫切需要。用50-60 Gy的电离辐射(IR)治疗GBM患者,并并发和
替莫唑胺(TMZ)的辅助化疗。辐射仍然仍然是最有效的疗法
GBM的方式,但这些肿瘤不可避免地会复发,并且复发性肿瘤对标准具有高度抗性
治疗。任何改善治疗都需要更好地理解GBM复发的基础和
复发性肿瘤的治疗耐药性。通过转基因鼠标模型从我们实验室发表的研究
确定IR是潜在的神经胶质素,并且在辐射暴露后引起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。这增加了通过放射治疗包含GBM细胞遗传改变的可能性
可以使复发性肿瘤难治性进一步治疗干预。我们实验室的令人兴奋的新结果
表明辐射还促进了与感应相关的秘书表型(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配体)。这表明辐射引起的正常脑细胞在附近的脑细胞的感应
肿瘤可能会改变微环境以促进肿瘤复发和放射线。翻译
我们实验室的重大结果表明,新型的“鼻溶剂”药物可以选择性地消除感官的星形胶质细胞
在大脑中,减轻SASP的促肿瘤效应。我们假设放疗诱导
GBM细胞中的遗传改变(例如,MET扩增)与感应相关的合作
大脑微环境(例如HGF分泌)的变化,以促进肿瘤复发和
放射线。我们建议分析“鼻溶液”是否可以选择性地杀死产生的感觉脑细胞
由于放疗,因此放射敏感GBM并延迟肿瘤复发。有紧急
需要实验策略来了解GBM和
开发翻译方法。我们已经开发了新型的患者衍生Xenographotic(PDX)和Syngeneic
为此目的,GBM复发的模型。使用这些模型和人类GBM标本,我们将
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,具有增强的DNA修复能力的癌症干细胞,(2)分泌如何
感觉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
感觉微环境可以用“鼻溶剂”药物否定,以改善GBM的结果
治疗。该项目可能导致制定有效的策略来治疗GBM
在放射疗法期间,考虑GBM细胞和脑微环境的变化。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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Sandeep Burma其他文献
Sandeep Burma的其他文献
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{{ truncateString('Sandeep Burma', 18)}}的其他基金
Enhancing MAPK-targeted Therapy in PDX Models of BRAF-Mutant Pediatric Brain Tumors
增强 BRAF 突变儿童脑肿瘤 PDX 模型中的 MAPK 靶向治疗
- 批准号:
10175336 - 财政年份:2021
- 资助金额:
$ 34.94万 - 项目类别:
Enhancing MAPK-targeted Therapy in PDX Models of BRAF-Mutant Pediatric Brain Tumors
增强 BRAF 突变儿童脑肿瘤 PDX 模型中的 MAPK 靶向治疗
- 批准号:
10368111 - 财政年份:2021
- 资助金额:
$ 34.94万 - 项目类别:
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
- 批准号:
10211559 - 财政年份:2021
- 资助金额:
$ 34.94万 - 项目类别:
Enhancing MAPK-targeted Therapy in PDX Models of BRAF-Mutant Pediatric Brain Tumors
增强 BRAF 突变儿童脑肿瘤 PDX 模型中的 MAPK 靶向治疗
- 批准号:
10553688 - 财政年份:2021
- 资助金额:
$ 34.94万 - 项目类别:
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
- 批准号:
10578763 - 财政年份:2021
- 资助金额:
$ 34.94万 - 项目类别:
Mechanisms of EXO1 regulation in response to radiation-induced DNA damage
EXO1 响应辐射引起的 DNA 损伤的调节机制
- 批准号:
9926813 - 财政年份:2019
- 资助金额:
$ 34.94万 - 项目类别:
Mechanisms of EXO1 regulation in response to radiation-induced DNA damage
EXO1 响应辐射引起的 DNA 损伤的调节机制
- 批准号:
10063785 - 财政年份:2019
- 资助金额:
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Augmented homologous recombination as a mechanism of acquired temozolomide resistance in glioblastoma
增强同源重组作为胶质母细胞瘤获得性替莫唑胺耐药的机制
- 批准号:
9325481 - 财政年份:2016
- 资助金额:
$ 34.94万 - 项目类别:
Molecular mechanisms of GBM radioresistance and strategies for radiosensitization
GBM放射抵抗的分子机制及放射增敏策略
- 批准号:
8605809 - 财政年份:2011
- 资助金额:
$ 34.94万 - 项目类别:
Molecular mechanisms of GBM radioresistance and strategies for radiosensitization
GBM放射抵抗的分子机制及放射增敏策略
- 批准号:
8042256 - 财政年份:2011
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