Dual Targeting of DNA Repair and p53 pathways for treatment of brain cancer
DNA 修复和 p53 通路双重靶向治疗脑癌
基本信息
- 批准号:8473057
- 负责人:
- 金额:$ 29.06万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-07-15 至 2015-05-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdultAffectAftercareAlkylating AgentsApoptosisBrainBrain NeoplasmsCancer PatientCaringCell Cycle ArrestCell DeathCell LineCell SurvivalCellsChemosensitizationChildhoodChimeric ProteinsClinicalCombined Modality TherapyCytotoxic agentDNA DamageDNA RepairDNA Repair PathwayDNA repair proteinDataDevelopmentDrug CombinationsDrug KineticsDrug toxicityE2F1 geneEGFR Gene AmplificationExposure toFrequenciesGenotoxic StressGlioblastomaGoalsGrowthHumanImaging technologyImplantIn VitroInvestigationKineticsLaboratoriesLeadLentivirus VectorLuciferasesMDM2 geneMalignant NeoplasmsMalignant neoplasm of brainMediatingModelingMolecular ProfilingMonitorMusNormal CellNormal tissue morphologyO(6)-Methylguanine-DNA MethyltransferaseOperative Surgical ProceduresOutcomePathway interactionsPatientsPharmaceutical PreparationsPharmacodynamicsPopulationPositioning AttributeProductionQuality of lifeRadiationRadiation Induced DNA DamageRadiation OncologyRadiation-Sensitizing AgentsRefractoryRegimenRegulationResearchResistanceSignal PathwaySignal TransductionSignal Transduction PathwaySignaling MoleculeTestingTherapeuticTimeTissuesToxic effectToxicologyTreatment EfficacyTreatment ProtocolsTreatment outcomeVascular Endothelial Growth FactorsXenograft Modelangiogenesisattenuationbasebioluminescence imagingcancer therapycancer typecell killingcell typeclinically relevantcombinatorialconventional therapycytotoxicitydrug efficacyeffective therapyexperiencehypoxia inducible factor 1improvedin vivoin vivo Modelinhibitor/antagonistirradiationkillingsmigrationmutantneoplastic cellnoveloutcome forecastpublic health relevanceresponsesenescencesmall moleculestemsuccesstemozolomidetreatment responsetreatment strategytumortumor microenvironmenttumor progressiontumor xenograftubiquitin-protein ligase
项目摘要
DESCRIPTION (provided by applicant): Development of efficacious strategies for treatment of glioblastoma multiforme (GBM) remains a significant challenge in both pediatric and adult patients. Some improvements, such as treatment with radiation and temozolomide (TMZ), have led to increased survival. However, the prognosis for brain tumor patients remains poor, and is largely due to the ability of these malignancies to acquire chemoresistance by modulation of p53-regulated signaling pathways that control cell survival. Our long-term goal is to develop therapeutic strategies that sensitize drug- and radiation-resistant brain tumors to therapy. In this proposal, we will investigate the efficacy of a novel combination therapy that targets the HDM2/p53 network and DNA repair. Inhibition of HDM2 interactions with key signaling molecules-p53, p73a, and HIF1a-by the small molecule inhibitor, nutlin3, can modulate their downstream effector function. Depending on the cell type studied, exposure to the HDM2 antagonist can lead to cell cycle arrest, senescence, apoptosis, decreased migration, and attenuation of VEGF production. To what extent TMZ and radiation in combination with nutlin3 can modulate these critical intracellular targets has not been studied. Our data indicate that nutlin3 can significantly potentiate TMZ- and radiation-mediated cytotoxicity in glioblastoma cells in vitro. In addition, nutlin3 also enhanced TMZ-mediated glioblastoma cell kill in an ectopic xenograft model. Our overall objective is to develop efficacious treatment strategies that kill brain tumor cells but not normal cells. For drug efficacy studies, ectopic and orthotopic glioblastomas will be established in NOD/SCID/IL2Rnull mice. A panel of established glioblastoma cell lines and early passaged glioblastoma primary cultures that differ in EGFR gene amplification, p53 status (wild-type or mutant), HDM2 status, MGMT expression, and sensitivities to TMZ and irradiation will be utilized. Real-time bioluminescence imaging will be utilized to serially monitor glioblastoma progression over time. Our central hypothesis is that nutlin3 potentiates the TMZ- and/or radiation-induced DNA damage response by perturbing HDM2-mediated regulation of key signaling molecules, and leads to increased glioblastoma cell death in vivo. To test this hypothesis, the following specific aims are proposed: 1) Develop therapeutic regimens and validate intracellular target modulation mediated by inhibition of HDM2-protein interactions during exposure to DNA-damaging agents 2) Assess in vivo the outcome of modulating HDM2-dependent signaling to increase therapeutic efficacy of TMZ- and/or radiation- mediated DNA damage. 3) Employ intracranial GBM xenograft models in combination with serial real- time bioluminescence imaging to monitor therapeutic impact of modulating HDM2-dependent signaling in combination with TMZ- and/or radiation-mediated DNA damage. The treatment strategies investigated here will use clinically relevant in vivo models and novel multi-targeting approaches and have the potential to improve treatment efficacy and quality of life for patients with GBM.
描述(由申请方提供):开发治疗多形性胶质母细胞瘤(GBM)的有效策略仍然是儿科和成人患者面临的重大挑战。一些改善,如放射治疗和替莫唑胺(TMZ),导致生存率增加。然而,脑肿瘤患者的预后仍然很差,这在很大程度上是由于这些恶性肿瘤通过调节控制细胞存活的p53调节的信号通路获得化学抗性的能力。我们的长期目标是开发治疗策略,使耐药和耐辐射的脑肿瘤对治疗敏感。在这项提案中,我们将研究一种针对HDM 2/p53网络和DNA修复的新型联合疗法的疗效。通过小分子抑制剂nutlin 3抑制HDM 2与关键信号分子p53、p73 a和HIF 1a的相互作用,可以调节其下游效应子功能。根据所研究的细胞类型,暴露于HDM 2拮抗剂可导致细胞周期停滞、衰老、凋亡、迁移减少和VEGF产生减弱。TMZ和辐射与nutlin 3组合可以在多大程度上调节这些关键的细胞内靶点尚未研究。我们的数据表明,nutlin 3可以显着增强TMZ和辐射介导的体外胶质母细胞瘤细胞的细胞毒性。此外,nutlin 3还增强了异位异种移植模型中TMZ介导的胶质母细胞瘤细胞杀伤。我们的总体目标是开发有效的治疗策略,杀死脑肿瘤细胞,而不是正常细胞。对于药物功效研究,将在NOD/SCID/IL 2 Rnull小鼠中建立异位和原位胶质母细胞瘤。将使用一组在EGFR基因扩增、p53状态(野生型或突变型)、HDM 2状态、MGMT表达和对TMZ和辐照敏感性方面不同的已建立胶质母细胞瘤细胞系和早期传代胶质母细胞瘤原代培养物。实时生物发光成像将用于连续监测胶质母细胞瘤随时间的进展。我们的中心假设是,nutlin 3通过扰乱HDM 2介导的关键信号分子调节来增强TMZ和/或辐射诱导的DNA损伤反应,并导致体内胶质母细胞瘤细胞死亡增加。为了检验这一假设,提出了以下具体目标:1)开发治疗方案并验证在暴露于DNA损伤剂期间通过抑制HDM 2-蛋白质相互作用介导的细胞内靶标调节; 2)体内评估调节HDM 2依赖性信号传导以增加TMZ和/或辐射介导的DNA损伤的治疗功效的结果。3)采用颅内GBM异种移植物模型与系列真实的-时间生物发光成像的组合,以监测调节HDM 2-依赖性信号传导与TMZ-和/或辐射介导的DNA损伤的组合的治疗影响。本文研究的治疗策略将使用临床相关的体内模型和新型多靶向方法,并有可能改善GBM患者的治疗疗效和生活质量。
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)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Karen Elizabeth Pollok其他文献
Karen Elizabeth Pollok的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Karen Elizabeth Pollok', 18)}}的其他基金
Dual Targeting of DNA Repair and p53 pathways for treatment of brain cancer
DNA 修复和 p53 通路双重靶向治疗脑癌
- 批准号:
7986836 - 财政年份:2010
- 资助金额:
$ 29.06万 - 项目类别:
Dual Targeting of DNA Repair and p53 pathways for treatment of brain cancer
DNA 修复和 p53 通路双重靶向治疗脑癌
- 批准号:
8110715 - 财政年份:2010
- 资助金额:
$ 29.06万 - 项目类别:
Dual Targeting of DNA Repair and p53 pathways for treatment of brain cancer
DNA 修复和 p53 通路双重靶向治疗脑癌
- 批准号:
8676458 - 财政年份:2010
- 资助金额:
$ 29.06万 - 项目类别:
相似海外基金
Co-designing a lifestyle, stop-vaping intervention for ex-smoking, adult vapers (CLOVER study)
为戒烟的成年电子烟使用者共同设计生活方式、戒烟干预措施(CLOVER 研究)
- 批准号:
MR/Z503605/1 - 财政年份:2024
- 资助金额:
$ 29.06万 - 项目类别:
Research Grant
Early Life Antecedents Predicting Adult Daily Affective Reactivity to Stress
早期生活经历预测成人对压力的日常情感反应
- 批准号:
2336167 - 财政年份:2024
- 资助金额:
$ 29.06万 - 项目类别:
Standard Grant
RAPID: Affective Mechanisms of Adjustment in Diverse Emerging Adult Student Communities Before, During, and Beyond the COVID-19 Pandemic
RAPID:COVID-19 大流行之前、期间和之后不同新兴成人学生社区的情感调整机制
- 批准号:
2402691 - 财政年份:2024
- 资助金额:
$ 29.06万 - 项目类别:
Standard Grant
Migrant Youth and the Sociolegal Construction of Child and Adult Categories
流动青年与儿童和成人类别的社会法律建构
- 批准号:
2341428 - 财政年份:2024
- 资助金额:
$ 29.06万 - 项目类别:
Standard Grant
Elucidation of Adult Newt Cells Regulating the ZRS enhancer during Limb Regeneration
阐明成体蝾螈细胞在肢体再生过程中调节 ZRS 增强子
- 批准号:
24K12150 - 财政年份:2024
- 资助金额:
$ 29.06万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Understanding how platelets mediate new neuron formation in the adult brain
了解血小板如何介导成人大脑中新神经元的形成
- 批准号:
DE240100561 - 财政年份:2024
- 资助金额:
$ 29.06万 - 项目类别:
Discovery Early Career Researcher Award
RUI: Evaluation of Neurotrophic-Like properties of Spaetzle-Toll Signaling in the Developing and Adult Cricket CNS
RUI:评估发育中和成年蟋蟀中枢神经系统中 Spaetzle-Toll 信号传导的神经营养样特性
- 批准号:
2230829 - 财政年份:2023
- 资助金额:
$ 29.06万 - 项目类别:
Standard Grant
Usefulness of a question prompt sheet for onco-fertility in adolescent and young adult patients under 25 years old.
问题提示表对于 25 岁以下青少年和年轻成年患者的肿瘤生育力的有用性。
- 批准号:
23K09542 - 财政年份:2023
- 资助金额:
$ 29.06万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Identification of new specific molecules associated with right ventricular dysfunction in adult patients with congenital heart disease
鉴定与成年先天性心脏病患者右心室功能障碍相关的新特异性分子
- 批准号:
23K07552 - 财政年份:2023
- 资助金额:
$ 29.06万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Issue identifications and model developments in transitional care for patients with adult congenital heart disease.
成人先天性心脏病患者过渡护理的问题识别和模型开发。
- 批准号:
23K07559 - 财政年份:2023
- 资助金额:
$ 29.06万 - 项目类别:
Grant-in-Aid for Scientific Research (C)