Markers of sensivity to the EGFR inhibitor erlotinib in breast cancer
乳腺癌中 EGFR 抑制剂厄洛替尼敏感的标志物
基本信息
- 批准号:7252750
- 负责人:
- 金额:$ 29.26万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-07-05 至 2012-05-31
- 项目状态:已结题
- 来源:
- 关键词:Adenovirus VectorAffectApoptosisBindingBiological AssayBiological MarkersBreastBreast Cancer CellBromodeoxyuridineCancer BiologyCancer PatientCell CycleCell NucleusCell ProliferationCellsClinicalCommunity Clinical Oncology ProgramConditionCytoplasmDevelopmentDiagnosticElementsEpidermal Growth FactorEpidermal Growth Factor ReceptorEpidermal Growth Factor Receptor Tyrosine Kinase InhibitorErlotinibFluorescence-Activated Cell SortingFreezingG1 PhaseGefitinibGenetic TranscriptionGoalsGrowth Factor ReceptorsImmunoblottingIn VitroKnowledgeLuc GeneMalignant neoplasm of lungMammary NeoplasmsMeasuresMediatingMedical OncologistMethodsModelingMolecularMolecular BiologyMolecular Mechanisms of ActionNorthern BlottingNuclearOutcomeParaffin EmbeddingPathologistPathway interactionsPatient SelectionPatientsPersonal SatisfactionPhasePhosphoproteinsPhosphorylationPhosphorylation SitePhosphotransferasesProtein OverexpressionProtein Tyrosine KinaseProteinsReadingReceptor SignalingRecruitment ActivityResearchResearch PersonnelResistanceRoleSamplingScanningSignal PathwaySignal TransductionSmall Interfering RNASoft Agar AssaySubgroupTechnologyThreonineTissue SampleTissuesTrainingTranslatingTyrosine Kinase InhibitorWorkXenograft Modelbasecancer therapycell growthclinically relevantcytotoxicitydesignexperiencehuman CDK2 proteinimprovedin vivoinsightmalignant breast neoplasmmutantnovelnovel therapeuticsp27 Cell Cycle Proteinp27 Enzyme Inhibitorprogramspromoterprotein degradationresistance mechanismresponsetooltumor
项目摘要
DESCRIPTION (provided by applicant): The epidermal growth factor receptor (EGFR) signaling pathway is a central regulator of cell growth and proliferation and modulates critical cell cycle regulatory molecules. This pathway has emerged as a promising target for cancer therapy. EGFR tyrosine kinase inhibitors (TKIs), such as erlotinib (Tarceva) and gefitinib (Iressa), are approved for cancer treatment but have induced a clinical response in only a subgroup of patients. Therefore, EGFR-TKI's molecular mechanism of action needs to be better understood. My long-term goal is to elucidate the molecular mechanism of action of EGFR-TKI so that novel therapeutic approaches or diagnostic tools that are clinically relevant can be developed. I have recently shown that in vitro erlotinib sensitivity is partially dependent on the activity of cyclin-dependent kinase 2 (Cdk2), which is the most downstream kinase of the EGFR pathway that regulates the transition from the G1 phase to the S phase. The objective of this application is to determine which downstream molecules of the EGFR and non-EGFR signaling pathway predict the response to EGFR-TKIs. The central hypothesis of this proposal is that the effect of Cdk2 activity on EGFR-TKI-mediated cytotoxicity is regulated by downstream molecules of the cell signaling pathway, specifically ERK, p27, and PEA15. This hypothesis is based on the following observations. First, erlotinib inhibits the tyrosine kinase of EGFR in both erlotinib-sensitive and erlotinib-resistant breast cancer cells; however, erlotinib inhibits Cdk2 activity only in sensitive cells. These findings indicate that there is an abnormality in the EGFR signaling pathway in erlotinib-resistant cells. Second, phosphorylated ERK is downregulated and p27 is upregulated in erlotinib-sensitive cells, and the phosphorylation status of p27 affects its nuclear-cytoplasmic localization and expression level. Third, PEA15 sequesters ERK into the cytoplasm from the nucleus and reduces cell proliferation. I have designed three independent but interrelated specific aims to provide a comprehensive assessment of the downstream EGFR and non-EGFR signaling pathway in breast cancer cells treated with EGFR-TKI. Specific Aim 1. Establish how erlotinib regulates p27 to suppress Cdk2 activity in vitro. Specific Aim 2. Establish how PEA15 modulates erlotinib sensitivity in vitro and in vivo. Specific Aim 3. Establish in vivo biomarkers that predict erlotinib sensitivity. Relevance: This study will provide significant insight into the role of downstream molecules affected by EGFR-TKI. Our findings will improve the outcome of cancer patients by increasing EGFR-TKI efficacy and facilitating the selection of patients who may benefit from EGFR-TKI therapy.
描述(申请人提供):表皮生长因子受体(EGFR)信号通路是细胞生长和增殖的中央调节因子,并调节关键的细胞周期调节分子。这一途径已成为癌症治疗的一个有希望的靶点。EGFR酪氨酸激酶抑制剂(TKIs),如erlotinib(Tarceva)和Gefitinib(Iressa),被批准用于癌症治疗,但只在一小部分患者中诱导了临床反应。因此,需要更好地了解EGFR-TKI的分子作用机制。我的长期目标是阐明EGFR-TKI的分子作用机制,以便开发出与临床相关的新的治疗方法或诊断工具。我最近发现,体外对厄洛替尼的敏感性部分依赖于细胞周期蛋白依赖性蛋白激酶2(CDK2)的活性,CDK2是EGFR通路中最下游的激酶,调节着从G1期到S期的转变。这项应用的目的是确定EGFR和非EGFR信号通路的哪些下游分子预测对EGFR-TKI的反应。这一建议的中心假设是,CDK2活性对EGFR-TKI介导的细胞毒作用的影响是由细胞信号通路的下游分子调控的,特别是ERK、p27和PEA15。这一假设基于以下观察结果。首先,厄洛替尼抑制对厄洛替尼敏感和耐药的乳腺癌细胞中EGFR的酪氨酸激酶;然而,厄洛替尼仅在敏感细胞中抑制CDK2活性。这些发现表明,在厄洛替尼耐药细胞中,EGFR信号通路存在异常。其次,在厄洛替尼敏感细胞中,磷酸化的ERK表达下调,p27表达上调,p27的磷酸化状态影响其核质定位和表达水平。第三,PEA15将ERK从细胞核隔离到细胞质中,从而减少了细胞增殖。我设计了三个独立但相互关联的特定目标,以提供对EGFR-TKI治疗的乳腺癌细胞中下游EGFR和非EGFR信号通路的全面评估。具体目的1.建立厄洛替尼在体外如何调节p27以抑制CDK2活性。具体目的2.建立PEA15如何在体外和体内调节厄洛替尼的敏感性。具体目的3.建立预测厄洛替尼敏感性的体内生物标志物。相关性:这项研究将对受EGFR-TKI影响的下游分子的作用提供重要的见解。我们的发现将通过增加EGFR-TKI的疗效和促进选择可能受益于EGFR-TKI治疗的患者来改善癌症患者的预后。
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)
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Naoto T Ueno其他文献
Navigating the androgen receptor landscape in triple-negative breast cancer
在三阴性乳腺癌中探索雄激素受体领域
- DOI:
10.1016/s1470-2045(25)00029-4 - 发表时间:
2025-03-01 - 期刊:
- 影响因子:35.900
- 作者:
Nithya Sridhar;Naoto T Ueno - 通讯作者:
Naoto T Ueno
Clinical outcomes after 1 versus 2-3 lines of neoadjuvant therapy in stage III inflammatory breast cancer.
III 期炎性乳腺癌 1 线与 2-3 线新辅助治疗后的临床结果。
- DOI:
- 发表时间:
2023 - 期刊:
- 影响因子:3.8
- 作者:
F. Nakhlis;Samuel M. Niman;Naoto T Ueno;Elizabeth Troll;Sean J. Ryan;E. Yeh;Laura Warren;J. Bellon;Beth Harrison;T. Iwase;H. T. Carisa Le;S. Saleem;M. Teshome;Gary J. Whitman;Wendy A Woodward;Beth Overmoyer;S. Tolaney;M. Regan;F. Lynce;R. Layman - 通讯作者:
R. Layman
Naoto T Ueno的其他文献
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{{ truncateString('Naoto T Ueno', 18)}}的其他基金
Developing a novel combination immunotherapy for triple-negative breast cancer
开发针对三阴性乳腺癌的新型联合免疫疗法
- 批准号:
10734197 - 财政年份:2023
- 资助金额:
$ 29.26万 - 项目类别:
Development of a novel therapy targeting the tumor microenvironment in inflammatory breast cancer
开发针对炎性乳腺癌肿瘤微环境的新疗法
- 批准号:
10836263 - 财政年份:2022
- 资助金额:
$ 29.26万 - 项目类别:
Development of a novel therapy targeting the tumor microenvironment in inflammatory breast cancer
开发针对炎性乳腺癌肿瘤微环境的新疗法
- 批准号:
10390676 - 财政年份:2022
- 资助金额:
$ 29.26万 - 项目类别:
Development of PEA 15 as a Targeted Therapeutic Gene for Ovarian Cancer
开发 PEA 15 作为卵巢癌靶向治疗基因
- 批准号:
8146139 - 财政年份:2007
- 资助金额:
$ 29.26万 - 项目类别:
Markers of sensivity to the EGFR inhibitor erlotinib in breast cancer
乳腺癌中 EGFR 抑制剂厄洛替尼敏感的标志物
- 批准号:
8265321 - 财政年份:2007
- 资助金额:
$ 29.26万 - 项目类别:
Markers of sensivity to the EGFR inhibitor erlotinib in breast cancer
乳腺癌中 EGFR 抑制剂厄洛替尼敏感的标志物
- 批准号:
7630446 - 财政年份:2007
- 资助金额:
$ 29.26万 - 项目类别:
Development of PEA 15 as a Targeted Therapeutic Gene for Ovarian Cancer
开发 PEA 15 作为卵巢癌靶向治疗基因
- 批准号:
7500877 - 财政年份:2007
- 资助金额:
$ 29.26万 - 项目类别:
Markers of sensivity to the EGFR inhibitor erlotinib in breast cancer
乳腺癌中 EGFR 抑制剂厄洛替尼敏感的标志物
- 批准号:
7462422 - 财政年份:2007
- 资助金额:
$ 29.26万 - 项目类别:
Development of PEA 15 as a Targeted Therapeutic Gene for Ovarian Cancer
开发 PEA 15 作为卵巢癌靶向治疗基因
- 批准号:
7894611 - 财政年份:2007
- 资助金额:
$ 29.26万 - 项目类别:
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