BRAFV600E and VEGFR2 synergize to trigger papillary thyroid cancer progression
BRAFV600E 和 VEGFR2 协同触发甲状腺乳头状癌进展
基本信息
- 批准号:9291440
- 负责人:
- 金额:$ 36.11万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-07-01 至 2019-05-31
- 项目状态:已结题
- 来源:
- 关键词:Acetyl-CoA CarboxylaseAngioinvasionAutocrine CommunicationAutomobile DrivingBAY 54-9085Biological MarkersCell AdhesionCell SurvivalCellsCellular Metabolic ProcessChIP-seqClinical TrialsCoculture TechniquesCollagenCombination Drug TherapyCombined Modality TherapyDataDevelopmentDoseDrug resistanceEarly DiagnosisEndothelial CellsExtracellular MatrixExtracellular Matrix ProteinsGenesGoalsGrowth Factor ReceptorsHumanImplantIn VitroIntegrin alpha ChainsIntegrinsKDR geneLinkLuciferasesMAPK3 geneMalignant neoplasm of lungMetabolicMetabolismMetastatic Neoplasm to Lymph NodesModelingMusMutationNeckNeoplasm MetastasisOralPapillary thyroid carcinomaParacrine CommunicationPathway interactionsPatientsPericytesPharmaceutical PreparationsPharmacotherapyPhosphorylationPhosphotransferasesPlayProcessPrognostic MarkerPropertyProteinsProteomicsRecruitment ActivityRecurrenceRefractoryReportingResearchResidual TumorsResidual stateResistanceRoleSCID MiceSamplingSignal PathwaySignal TransductionSpecimenSurvival RateSystemTNFSF15 geneTestingThyroid GlandTreatment EfficacyUp-RegulationVEGFA geneanaplastic thyroid cancerangiogenesisautocrinebasebiomarker developmentcancer cellcancer therapycell motilitydensitydrug developmentimprovedin vitro Assayinhibitor/antagonistinsightknock-downmelanomamigrationmortalitymouse modelnew therapeutic targetnovelnovel markernovel therapeuticsoutcome forecastoverexpressionparacrinepre-clinicalprotein Eprotein expressionpublic health relevanceradioiodine therapyreceptorresistance mechanismresponsescreeningsmall hairpin RNAstandard caresynergismtargeted treatmenttranscription factortumortumor growthtumor microenvironmenttumor progression
项目摘要
DESCRIPTION (provided by applicant): Papillary thyroid cancer (PTC) typically has a favorable prognosis; however, patients with PTC carrying the BRAFV600E mutation show resistance to radioiodine treatment and have high rates of metastases and low survival rates. Inhibitors of BRAFV600E, including vemurafenib, have been tested recently as treatments for BRAFV600E-melanomas, with very promising results. However, development of secondary tumor resistance to these compounds has been reported. Another potential player in PTC aggressiveness is vascular endothelial growth factor receptor 2 (VEGFR2), a crucial regulator of angiogenesis. Sorafenib, which targets VEGFR2, was only partially effective against metastatic PTC, suggesting secondary resistance mechanisms to this drug as well. Our preliminary results show that metastatic primary human BRAFV600E positive PTC cells in vitro were resistant to high doses of either vemurafenib or sorafenib alone, but combined treatment with both drugs decreased cell viability by greater than 90%. BRAFV600E up-regulates VEGFR2 and pERK1/2 in PTC cells, triggering recruitment of endothelial cells and pericytes. We also observed upregulation of ACAC� (metabolic gene) suggesting that BRAFV600E harnesses a metabolic response that promotes PTC metastasis, a novel mechanism. Our preliminary data also indicate that VEGFR2 is associated with neck recurrence in BRAFV600E PTC. Our objective is to determine how BRAFV600E and VEGFR2 fit into the autocrine and paracrine signaling pathways that control PTC cell progression. Our central hypothesis is that BRAFV600E and VEGFR2 pathways synergize in PTC cells, increasing secretion of extracellular matrix (ECM) proteins and leading to increased PTC cell adhesion, migration/invasion, and angiogenesis. We propose a secondary pathway in which the BRAFV600E/ERK1/2 signaling cascade triggers hyper-expression of VEGFR2 in PTC cells. The alternate VEGFR2 pathway synergizes with residual BRAFV600E activity in the presence of vemurafenib, conferring secondary drug resistance in PTC cells. We will test this by manipulating VEGFR2 and BRAFV600E function and assessing tumorogenic properties in our novel models: a 3D co-culture system that recapitulates the PTC microenvironment, an orthotopic mouse with primary human PTC cells with heterozygous BRAFWT/V600E, and ChIp-seq analysis. Aim 1: To elucidate the autocrine and paracrine pathways by which BRAFV600E and VEGFR2 promote PTC aggressiveness. These studies will delineate VEGFR2-interacting ECM proteins that enhance ERK1/2 phosphorylation in BRAFV600E PTC and provide new insight into vemurafenib and sorafenib secondary drug resistance. Aim 2: To assess whether VEGFR2 protein expression is a long-term prognostic biomarker for PTC aggressiveness in BRAFV600E PTC. Aim 3: To assess efficacy of anti-BRAFV600E and anti-VEGFR2 combined therapy in a pre-clinical mouse model of human heterozygous BRAFWT/V600E PTC. These proposed studies are highly likely to provide evidence supporting clinical trials of combined targeted therapy for BRAFV600E-PTC and identify novel targets for drug development and biomarkers for aggressive PTC.
描述(由申请人提供):甲状腺乳头状癌(PTC)通常预后良好;然而,携带BRAFV600E突变的PTC患者对放射性碘治疗表现出耐药性,转移率高,生存率低。BRAFV600E抑制剂,包括vemurafenib,最近已经作为BRAFV600E黑色素瘤的治疗方法进行了测试,并取得了非常有希望的结果。然而,已报道了对这些化合物的继发性肿瘤耐药的发展。PTC侵袭性的另一个潜在参与者是血管内皮生长因子受体2 (VEGFR2),它是血管生成的重要调节因子。靶向VEGFR2的索拉非尼对转移性PTC仅部分有效,这也表明该药物的继发性耐药机制。我们的初步结果显示,转移性原发人BRAFV600E阳性PTC细胞体外对单独使用vemurafenib或索拉非尼的高剂量耐药,但联合使用这两种药物可使细胞活力降低90%以上。BRAFV600E上调PTC细胞中的VEGFR2和pERK1/2,触发内皮细胞和周细胞的募集。我们还观察到ACAC(代谢基因)的上调,这表明BRAFV600E利用代谢反应促进PTC转移,这是一种新机制。我们的初步数据还表明,VEGFR2与BRAFV600E PTC的颈部复发有关。我们的目标是确定BRAFV600E和VEGFR2如何适应控制PTC细胞进展的自分泌和旁分泌信号通路。我们的中心假设是BRAFV600E和VEGFR2通路在PTC细胞中协同作用,增加细胞外基质(ECM)蛋白的分泌,导致PTC细胞粘附、迁移/侵袭和血管生成增加。我们提出了BRAFV600E/ERK1/2信号级联触发PTC细胞中VEGFR2超表达的次要途径。在vemurafenib存在下,VEGFR2替代途径与残留的BRAFV600E活性协同作用,在PTC细胞中产生继发性耐药。我们将通过操纵VEGFR2和BRAFV600E功能来测试这一点,并在我们的新模型中评估致瘤特性:再现PTC微环境的3D共培养系统,具有原代人PTC细胞的原位小鼠,杂合BRAFWT/V600E,以及ChIp-seq分析。目的1:阐明BRAFV600E和VEGFR2促进PTC侵袭性的自分泌和旁分泌途径。这些研究将描述vegfr2相互作用的ECM蛋白在BRAFV600E PTC中增强ERK1/2磷酸化,并为vemurafenib和sorafenib继发性耐药提供新的见解。目的2:评估VEGFR2蛋白表达是否为BRAFV600E PTC患者PTC侵袭性的长期预后生物标志物。目的3:评估抗brafv600e和抗vegfr2联合治疗在人杂合子BRAFWT/V600E PTC临床前小鼠模型中的疗效。这些拟议的研究极有可能为BRAFV600E-PTC联合靶向治疗的临床试验提供证据,并为侵袭性PTC的药物开发和生物标志物确定新的靶点。
项目成果
期刊论文数量(0)
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Carmelo Nucera其他文献
Carmelo Nucera的其他文献
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{{ truncateString('Carmelo Nucera', 18)}}的其他基金
Role of newly identified, thyroid-specific LincRNA in BRAFV600E thyroid carcinoma
新发现的甲状腺特异性 LincRNA 在 BRAFV600E 甲状腺癌中的作用
- 批准号:
10582558 - 财政年份:2020
- 资助金额:
$ 36.11万 - 项目类别:
Role of newly identified, thyroid-specific LincRNA in BRAFV600E thyroid carcinoma
新发现的甲状腺特异性 LincRNA 在 BRAFV600E 甲状腺癌中的作用
- 批准号:
10368959 - 财政年份:2020
- 资助金额:
$ 36.11万 - 项目类别:
BRAFV600E and VEGFR2 synergize to trigger papillary thyroid cancer progression
BRAFV600E 和 VEGFR2 协同触发甲状腺乳头状癌进展
- 批准号:
8728483 - 财政年份:2014
- 资助金额:
$ 36.11万 - 项目类别:
BRAFV600E and VEGFR2 synergize to trigger papillary thyroid cancer progression
BRAFV600E 和 VEGFR2 协同触发甲状腺乳头状癌进展
- 批准号:
9065513 - 财政年份:2014
- 资助金额:
$ 36.11万 - 项目类别:
Metastatic protein network in BRAFV600E positive human thyroid cancers
BRAFV600E 阳性人类甲状腺癌的转移蛋白网络
- 批准号:
8507182 - 财政年份:2012
- 资助金额:
$ 36.11万 - 项目类别:
Metastatic protein network in BRAFV600E positive human thyroid cancers
BRAFV600E 阳性人类甲状腺癌的转移蛋白网络
- 批准号:
8386065 - 财政年份:2012
- 资助金额:
$ 36.11万 - 项目类别: