Improving treatment of brain metastases from HER2-positive breast cancer
改善 HER2 阳性乳腺癌脑转移的治疗
基本信息
- 批准号:8864389
- 负责人:
- 金额:$ 39.8万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-04-01 至 2016-03-31
- 项目状态:已结题
- 来源:
- 关键词:AftercareAnimal ModelAntibodiesBiological MarkersBrainBrain NeoplasmsBreastBreast Cancer CellBreast Cancer cell lineCell ProliferationCell SurvivalCellsCerebrumClinicalClinical TrialsCombined Modality TherapyComparative StudyDevelopmentDimerizationDrug TargetingERBB2 geneERBB3 geneFamily memberFatty acid glycerol estersFutureGenetic ModelsGrowthHER2 inhibitionHeterodimerizationHumanImaging TechniquesImaging technologyImplantIn VitroInhibition of ApoptosisLesionLigandsMAP Kinase GeneMammary glandMeasuresMediatingMetabolicMetastatic breast cancerMetastatic malignant neoplasm to brainModelingMolecularMorbidity - disease rateMusNeoplasm MetastasisNeuregulin 1Pathway interactionsPatientsPharmaceutical PreparationsPhosphorylationPrimary NeoplasmProductionResistanceResolutionRoleSignal TransductionSiteSliceSurvival RateSystemic diseaseTechniquesTestingTherapeuticTissuesTransgenic MiceTrastuzumabattenuationcancer cellclinically relevantcombinatorialdesigneffective therapyefficacy testingglucose uptakehuman FRAP1 proteinhuman tissueimprovedin vivoinhibitor/antagonistinsightmalignant breast neoplasmmeetingsmouse modelmultidisciplinaryneoplastic cellnew therapeutic targetnoveloutcome forecastoverexpressionpalliativepreclinical studypublic health relevanceresearch studyresponsetargeted treatmenttranslational studytreatment responsetreatment strategytumortumor growth
项目摘要
DESCRIPTION (provided by applicant): Treatment of cerebral metastases of HER2-positive (HER2+) breast cancer remains an unmet need. The development of novel HER2 targeting agents has revolutionized the treatment of HER2+ systemic disease; however, the efficacy of these targeted drugs is very limited in the brain microenvironment. Treatment is palliative in the majority of the cases, with survival rates varying between 4-12 months. This poor prognosis emphasizes the urgent need to unravel the mechanisms that underlie resistance of brain metastases (BM) to HER2 targeted drugs, in order to optimize therapeutic approaches in this setting. Recent preclinical studies indicate that ErbB3 (HER3) has a central role in promoting resistance to HER2 targeted therapies. We have discovered that HER3 and its activating ligand neuregulin-1 (NRG-1) are highly expressed in HER2+ breast cancer BM. Moreover, we have found that HER3 blockade enhances the efficacy of anti-HER2 therapy in the brain, resulting in significant tumor growth delay and improved survival. Building on these exciting preliminary findings, we now propose to unravel the mechanisms involved in HER3-mediated resistance to HER2 inhibition in the brain using well-characterized primary and patient-derived human HER2+ breast cancer cell lines, transgenic mouse models, and state-of-the-art imaging techniques. In Aim 1, we will examine the molecular mechanisms of NRG-1-dependent HER3 activation in the brain microenvironment. In Aim 2, we will investigate how the NRG-HER3 axis mediates resistance to anti-HER2 therapies. Lastly, in Aim 3 we will determine the effects of combinatorial NRG-1/HER3 and HER2 pathway inhibition in translational studies using brain metastasis models. To realize these aims, we have developed clinically relevant animal models of breast cancer BM, and powerful, non-invasive, high resolution imaging technologies that provide unprecedented molecular, cellular, structural and functional insights, and reveal various steps of BM progression. We will use these techniques and the unique collective expertise of our multidisciplinary team to uncover the role of the NRG-1/HER3 axis in mediating resistance to HER2 targeted therapies. Furthermore, we will validate the therapeutic benefit of combinatorial treatment strategies, which will directly inform clinical trials in patients with HER2+ breast cancr brain metastases, and will meet the urgent need for effective therapies.
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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Rakesh K. Jain其他文献
In vitro and in vivo quantification of adhesion between leukocytes and vascular endothelium.
白细胞和血管内皮之间粘附的体外和体内定量。
- DOI:
10.1385/0-89603-516-6:553 - 发表时间:
1999 - 期刊:
- 影响因子:0
- 作者:
Rakesh K. Jain;L. Munn;D. Fukumura;R. Melder - 通讯作者:
R. Melder
Xanthan gum: an economical substitute for agar in plant tissue culture media
黄原胶:植物组织培养基中琼脂的经济替代品
- DOI:
- 发表时间:
2006 - 期刊:
- 影响因子:6.2
- 作者:
Rakesh K. Jain;S. Babbar - 通讯作者:
S. Babbar
Anaerobes in bacterial vaginosis.
细菌性阴道病中的厌氧菌。
- DOI:
- 发表时间:
2003 - 期刊:
- 影响因子:1.6
- 作者:
A. Aggarwal;P. Devi;Rakesh K. Jain - 通讯作者:
Rakesh K. Jain
Leveraging insights from cancer to improve tuberculosis therapy
利用癌症研究的见解来改进结核病治疗
- DOI:
10.1016/j.molmed.2024.07.011 - 发表时间:
2025-01-01 - 期刊:
- 影响因子:13.800
- 作者:
Meenal Datta;Laura E. Via;Véronique Dartois;Lei Xu;Clifton E. Barry;Rakesh K. Jain - 通讯作者:
Rakesh K. Jain
Herceptin acts as an anti-angiogenic cocktail
赫赛汀(Herceptin)起着抗血管生成鸡尾酒的作用
- DOI:
10.1038/416279b - 发表时间:
2002-03-21 - 期刊:
- 影响因子:48.500
- 作者:
Yotaro Izumi;Lei Xu;Emmanuelle di Tomaso;Dai Fukumura;Rakesh K. Jain - 通讯作者:
Rakesh K. Jain
Rakesh K. Jain的其他文献
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{{ truncateString('Rakesh K. Jain', 18)}}的其他基金
Reprogramming the tumormicroenvironment to improve immunotherapy of glioblastoma
重新编程肿瘤微环境以改善胶质母细胞瘤的免疫治疗
- 批准号:
10595045 - 财政年份:2022
- 资助金额:
$ 39.8万 - 项目类别:
Reprogramming the tumormicroenvironment to improve immunotherapy of glioblastoma
重新编程肿瘤微环境以改善胶质母细胞瘤的免疫治疗
- 批准号:
10417806 - 财政年份:2022
- 资助金额:
$ 39.8万 - 项目类别:
Improving treatment of HER2+ breast cancer brain metastasis by targeting lipid metabolism
通过靶向脂质代谢改善 HER2 乳腺癌脑转移的治疗
- 批准号:
10185953 - 财政年份:2021
- 资助金额:
$ 39.8万 - 项目类别:
Improving treatment of HER2+ breast cancer brain metastasis by targeting lipid metabolism
通过靶向脂质代谢改善 HER2 乳腺癌脑转移的治疗
- 批准号:
10397627 - 财政年份:2021
- 资助金额:
$ 39.8万 - 项目类别:
Improving treatment of HER2+ breast cancer brain metastasis by targeting lipid metabolism
通过靶向脂质代谢改善 HER2 乳腺癌脑转移的治疗
- 批准号:
10620649 - 财政年份:2021
- 资助金额:
$ 39.8万 - 项目类别:
Targeting physical stress-driven mechanisms to overcome glioblastoma treatment resistance
针对物理压力驱动机制克服胶质母细胞瘤治疗耐药性
- 批准号:
10696949 - 财政年份:2021
- 资助金额:
$ 39.8万 - 项目类别:
Targeting physical stress-driven mechanisms to overcome glioblastoma treatment resistance
针对物理压力驱动机制克服胶质母细胞瘤治疗耐药性
- 批准号:
10273309 - 财政年份:2021
- 资助金额:
$ 39.8万 - 项目类别:
Dissecting Pediatric Brain Tumor Microenvironment to Improve Treatment
剖析小儿脑肿瘤微环境以改善治疗
- 批准号:
9334783 - 财政年份:2015
- 资助金额:
$ 39.8万 - 项目类别:
Dissecting Pediatric Brain Tumor Microenvironment to Improve Treatment
剖析小儿脑肿瘤微环境以改善治疗
- 批准号:
9766197 - 财政年份:2015
- 资助金额:
$ 39.8万 - 项目类别:
Overcoming Resistance to Anti-VEGF Treatment of Glioblastoma
克服胶质母细胞瘤抗 VEGF 治疗的耐药性
- 批准号:
8463131 - 财政年份:2013
- 资助金额:
$ 39.8万 - 项目类别:
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