The role of Nrf2 in mediating resistance to EGFR inhibition in glioblastoma
Nrf2 在介导胶质母细胞瘤对 EGFR 抑制的抵抗中的作用
基本信息
- 批准号:10615766
- 负责人:
- 金额:$ 36.76万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-06-01 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:AddressBiologicalCell Culture TechniquesCell DeathCellsCellular StressChemotherapy and/or radiationClinicalColon CarcinomaDataDiseaseEGFR Gene AmplificationEGFR geneEpidermal Growth Factor ReceptorEpidermal Growth Factor Receptor Tyrosine Kinase InhibitorErlotinibEstrogen ReceptorsExperimental ModelsFDA approvedFailureFrequenciesGene MutationGenesGenetic TranscriptionGlioblastomaGliomaGliomagenesisGrowthHomeostasisImmunotherapyInterruptionLigandsMalignant NeoplasmsMalignant neoplasm of lungMediatingMediatorMeningeal TuberculosisModelingMusMutationOncogenesOncogenicPathway interactionsPatientsPlayPrevalencePrognosisRadiation therapyReceptor InhibitionReceptor SignalingRecommendationReportingResistanceRoleSignal TransductionTNF geneTamoxifenTestingTranscriptional ActivationTranslationsTrastuzumabTumor TissueWorkcancer cellcancer therapyclinically relevanteffective therapyepidermal growth factor receptor VIIIimprovedinhibitorisoniazidmalignant breast neoplasmmutantneoplastic celloverexpressionpre-clinicalpreventreceptor expressionresistance mechanismresponsetargeted treatmenttherapy resistanttranscription factortranscriptometumortumor growth
项目摘要
Inhibition of epidermal growth factor receptor (EGFR) signaling is an important approach to the targeted
treatment of cancer. However, although aberrant EGFR signaling is widespread in cancer, EGFR inhibition is
primarily effective only in a limited number of lung cancers that express specific EGFR mutations and are
oncogene addicted. Thus, the ability to render cancer cells with primary EGFR resistance sensitive to EGFR
inhibition is potentially of enormous clinical value, given the wide prevalence of EGFR overexpressing cancers
with primary resistance to EGFR inhibition. Aberrant epidermal growth factor receptor (EGFR) signaling is
common in glioblastoma (GBM). GBM is a devastating disease and, even with the best treatment, the
prognosis is dismal. No targeted treatment is effective in GBM. EGFR gene amplification and mutation are
common in GBM and multiple trials of EGFR inhibition in GBM have been conducted. However, EGFR
inhibition has not been successful in GBM. The failure of targeted treatments in GBM has led to an intensive
effort to understand mechanisms that mediate resistance to targeted treatment. Here, we propose a
mechanism that mediates primary resistance to EGFR inhibition in GBM and a strategy to overcome it. We
propose that the primary resistance of EGFR expressing GBMs results from a rapid adaptive response that
prevents cell death from a sudden loss of EGFR signaling. This adaptive response can be detected in glioma
cells expressing either EGFRwt or the oncogenic EGFRvIII mutant. Our preliminary data indicate that in
glioma cells expressing either EGFRwt or EGFRvIII, Erlotinib triggers a rapid homeostatic response that
involves activation of the transcription factor Nrf2 signaling network. Nrf2 regulates key downstream signaling
networks that are critical mediators of therapeutic resistance to EGFR inhibition in GBM. Our preliminary data
indicate that a combined inhibition of EGFR and Nrf2 overcomes the primary resistance of GBMs to EGFR
inhibition in cell culture as well as in an orthotopic model of GBM. In Specific Aim 1: we examine the effector
mechanisms downstream of Nrf2 that mediate mediating primary resistance to EGFR inhibition in glioma cells
In Specific Aim 2 we examine the mechanisms that regulate activation of Nrf2 in response to EGFR inhibition
in GBM. In Specific Aim 3 we examine the biological effect of combined inhibition of EGFR and Nrf2 or
inhibition of key signaling networks downstream of Nrf2 in a preclinical mouse orthotopic model examining the
hypothesis that interruption of adaptive survival signaling triggered by EGFR inhibition will transform GBMs
with primary resistance into cancers that can be effectively treated by EGFR inhibition. Since both EGFR and
Nrf2 inhibitors are in clinical use, this approach could be rapidly tested in patients. The proposal addresses
critical unmet needs in the management of GBM, and could have a transformative impact on the way GBM is
treated.
抑制表皮生长因子受体(EGFR)信号转导是靶向治疗的重要途径
癌症的治疗。然而,尽管异常的EGFR信号在癌症中广泛存在,但EGFR抑制
主要只对有限数量的表达特定EGFR突变的肺癌有效,并且
癌基因成瘾。因此,使具有原代EGFR耐药的癌细胞对EGFR敏感的能力
考虑到egfr过度表达癌症的广泛流行,抑制具有潜在的临床价值。
具有对EGFR抑制的原发耐药性。表皮生长因子受体(EGFR)异常信号转导
常见于胶质母细胞瘤(GBM)。GBM是一种毁灭性的疾病,即使有最好的治疗,
预后很差。对于GBM,没有靶向治疗是有效的。EGFR基因扩增和突变
在GBM中很常见,并且已经进行了多项关于抑制GBM中EGFR的试验。然而,EGFR
在GBM中,抑制作用并不成功。GBM靶向治疗的失败导致了密集的
努力了解介导靶向治疗耐药的机制。在这里,我们提出一种
GBM对EGFR抑制的原发耐药机制及其克服策略。我们
认为EGFR表达GBMS的主要抗性是快速适应反应的结果
防止细胞因突然失去EGFR信号而死亡。这种适应性反应可以在胶质瘤中检测到。
表达EGFRwt或致癌EGFRvIII突变体的细胞。我们的初步数据显示,
表达EGFRwt或EGFRvIII,Erlotinib的胶质瘤细胞触发快速稳态反应,
涉及转录因子Nrf2信号网络的激活。NRF2调节关键下行信令
这些网络是GBM对EGFR抑制的治疗抵抗的关键媒介。我们的初步数据
提示EGFR和Nrf2的联合抑制克服了GBM对EGFR的原发耐药性
在细胞培养中的抑制以及在GBM的原位模型中。具体目标1:我们检查效应器
Nrf2下游介导胶质瘤细胞对EGFR抑制的原发耐药机制
在特定的目标2中,我们研究了调节Nrf2激活以响应EGFR抑制的机制
单位为GBM。在特定的目标3中,我们检测了联合抑制EGFR和Nrf2或
在临床前小鼠原位模型中抑制Nrf2下游的关键信号网络
假设EGFR抑制触发的适应性生存信号的中断将改变基底膜
具有原发耐药性的癌症可以通过抑制EGFR有效地治疗。由于EGFR和
NRF2抑制剂正在临床使用,这种方法可以在患者身上快速测试。该提案涉及
GBM管理中未得到满足的关键需求,并可能对GBM的方式产生变革性影响
治疗过了。
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Elimination of Radiation-Induced Senescence in the Brain Tumor Microenvironment Attenuates Glioblastoma Recurrence.
消除脑肿瘤微环境中辐射诱导的衰老会减轻胶质母细胞瘤的复发。
- DOI:10.1158/0008-5472.can-21-0752
- 发表时间:2021-12-01
- 期刊:
- 影响因子:11.2
- 作者:
- 通讯作者:
Tumor necrosis factor in lung cancer: Complex roles in biology and resistance to treatment.
- DOI:10.1016/j.neo.2020.12.006
- 发表时间:2021-03
- 期刊:
- 影响因子:0
- 作者:Gong K;Guo G;Beckley N;Zhang Y;Yang X;Sharma M;Habib AA
- 通讯作者:Habib AA
Intrapleural nano-immunotherapy promotes innate and adaptive immune responses to enhance anti-PD-L1 therapy for malignant pleural effusion.
- DOI:10.1038/s41565-021-01032-w
- 发表时间:2022-03
- 期刊:
- 影响因子:38.3
- 作者:
- 通讯作者:
Itraconazole Exerts Its Antitumor Effect in Esophageal Cancer By Suppressing the HER2/AKT Signaling Pathway.
- DOI:10.1158/1535-7163.mct-20-0638
- 发表时间:2021-10
- 期刊:
- 影响因子:5.7
- 作者:Zhang W;Bhagwath AS;Ramzan Z;Williams TA;Subramaniyan I;Edpuganti V;Kallem RR;Dunbar KB;Ding P;Gong K;Geurkink SA;Beg MS;Kim J;Zhang Q;Habib AA;Choi SH;Lapsiwala R;Bhagwath G;Dowell JE;Melton SD;Jie C;Putnam WC;Pham TH;Wang DH
- 通讯作者:Wang DH
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{{ truncateString('AMYN HABIB', 18)}}的其他基金
The role of Nrf2 in mediating resistance to EGFR inhibition in glioblastoma
Nrf2 在介导胶质母细胞瘤对 EGFR 抑制的抵抗中的作用
- 批准号:
10404075 - 财政年份:2020
- 资助金额:
$ 36.76万 - 项目类别:
Interactions between inflammatory and oncogenic signaling pathways in GBM
GBM 炎症和致癌信号通路之间的相互作用
- 批准号:
8735239 - 财政年份:2014
- 资助金额:
$ 36.76万 - 项目类别:
Interactions between inflammatory and oncogenic signaling pathways in GBM
GBM 炎症和致癌信号通路之间的相互作用
- 批准号:
10266003 - 财政年份:2014
- 资助金额:
$ 36.76万 - 项目类别:
Interactions between inflammatory and oncogenic signaling pathways in GBM
GBM 炎症和致癌信号通路之间的相互作用
- 批准号:
9339563 - 财政年份:2014
- 资助金额:
$ 36.76万 - 项目类别:
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