Microenvironment mediated drug resistance in melanoma.
微环境介导黑色素瘤耐药性。
基本信息
- 批准号:8163854
- 负责人:
- 金额:$ 34.65万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-08-01 至 2016-05-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdhesionsAdoptionApoptosisBRAF geneBeliefBlood VesselsBypassCell LineCellsClinicClinicalClinical TrialsCoculture TechniquesCollagenDataDepositionDrug resistanceEffectivenessEndothelial CellsEnvironmentExtracellular MatrixFibroblastsFibronectinsFutureGenotypeGoalsGrowthGrowth FactorHeterogeneityHumanIntegrinsKnowledgeLamininLeadLifeLigandsMEKsMediatingMelanoma CellMinorModelingMutatePTEN genePatientsPhasePhenotypePlatelet-Derived Growth FactorPopulationProliferatingProto-Oncogene Proteins c-aktRelapseResearchResistanceRoleSeriesSignal TransductionSpecimenTestingTherapeuticVascular Endothelial Growth FactorsWorkXenograft Modelangiogenesisautocrinecell motilityimprovedin vivoinhibitor/antagonistmelanomaneoplastic cellnotch proteinnovelnovel therapeuticspreventresearch studyresistance mechanismresponsesmall moleculetherapeutic developmenttherapeutic targettumortumor eradication
项目摘要
DESCRIPTION (provided by applicant): The long-term goals of this work are the development of therapeutic strategies to improve the survival of patients with disseminated melanoma. There is already good evidence that mutated BRAF is a bona fide therapeutic target in over 50% of melanomas, and that impressive but short-lived clinical responses can be achieved with small molecule BRAF inhibitors (such as PLX4032). Clinically, BRAF inhibitor resistance follows a course where tumor regression is followed by quiescence and eventual relapse. The overall hypothesis is that BRAF inhibition remodels both the melanoma and host microenvironments to provide a protective "sanctuary" for the minor populations of melanoma cells that escape therapy. Conceptually, it is believed that there are at least two forms of environment-mediated therapeutic escape; the first, defined as "tumor intrinsic", was observed in melanoma cell lines that lack PTEN function (PTEN-) and involved the establishment of autocrine integrin/extracellular matrix (ECM) signaling loops that bypass BRAF signaling and downregulate apoptosis. The second was host-mediated, where BRAF inhibition in primary human fibroblasts paradoxically activated AKT and MEK signaling leading to the expression of PDGF-D, VEGF and the Notch ligand Jagged as well as increasing the deposition of fibronectin, collagens and laminin. The first aim will investigate how BRAF inhibition leads to the acquisition of autocrine ECM-driven signaling loops and will determine how these altered adhesion signals "re-wire" the signaling of the escaping population and leads to the adoption of a phenotype that is slow-proliferating, apoptosis resistant and pro-invasive. We will then test whether therapeutic targeting of the melanoma cell/ECM interactions ameliorates intrinsic resistance by preventing the microenvironment- mediated reorganization of the melanoma signaling network. In aim 2, we will test the hypothesis that BRAF inhibition activates host fibroblasts leading to the creation of a "refuge" vascular microenvironment that allows PTEN+ melanoma cells to escape from therapy. We will address how BRAF inhibition in normal host fibroblasts leads to the establishment of autocrine growth factor signaling loops that drives their activation. We will then use novel 3D melanoma/fibroblast/endothelial cell co-culture and in vivo xenograft models to investigate the mechanisms by which inhibition of BRAF in fibroblasts drives the angiogenic response and will elucidate the role of the vascular niche as a protective "sanctuary" for the escaping melanoma cells. It is expected that knowledge gained from this work will provide novel therapeutic strategies for overcoming BRAF inhibitor resistance in the clinic. 1
PUBLIC HEALTH RELEVANCE: Although small molecule BRAF inhibitors are showing great promise as novel melanoma therapies, their effectiveness is severely limited by both acquired and intrinsic drug resistance. The aim of the proposal is to elucidate the mechanisms by which the host and tumor microenvironments contribute towards both of these resistance mechanisms. We expect this research to define novel microenvironment-directed strategies for delaying and abrogating drug resistance in melanoma that can be evaluated in future clinical trials.
描述(由申请人提供):这项工作的长期目标是开发治疗策略,以提高播散性黑色素瘤患者的存活率。已经有很好的证据表明,突变的BRAF是超过50%的黑色素瘤的真正治疗靶点,小分子BRAF抑制剂(如PLX4032)可以达到令人印象深刻但短暂的临床反应。在临床上,BRAF抑制剂抵抗遵循一个过程,肿瘤消退之后是静止和最终复发。总体假设是,BRAF抑制改变了黑色素瘤和宿主微环境,为逃脱治疗的少数黑色素瘤细胞提供了保护性的“避难所”。从概念上讲,人们认为至少有两种形式的环境介导的治疗逃逸:第一种被定义为“肿瘤固有的”,在缺乏PTEN功能的黑色素瘤细胞系中观察到,涉及建立自分泌整合素/细胞外基质(ECM)信号环,绕过BRAF信号,下调细胞凋亡。第二种是宿主介导的,在原代培养的人成纤维细胞中,BRAF的抑制矛盾地激活了AKT和MEK信号,导致PDGF-D、VEGF和Notch配体的表达呈锯齿状,并增加了纤维连接蛋白、胶原和层粘连蛋白的沉积。第一个目标是研究BRAF抑制如何导致自分泌ECM驱动的信号环的获得,并将确定这些改变的黏附信号如何重新连接逃逸群体的信号,并导致采用一种缓慢增殖、抗凋亡和亲侵袭的表型。然后,我们将测试黑色素瘤细胞/细胞外基质相互作用的治疗靶点是否通过阻止微环境介导的黑色素瘤信号网络的重组来改善内在耐药性。在目标2中,我们将验证这样一个假设,即BRAF抑制激活宿主成纤维细胞,从而创建一个允许PTEN+黑色素瘤细胞逃脱治疗的“避难所”血管微环境。我们将讨论在正常宿主成纤维细胞中抑制BRAF如何导致自分泌生长因子信号环的建立,从而驱动其激活。然后,我们将使用新的3D黑色素瘤/成纤维细胞/内皮细胞共培养和体内异种移植模型来研究抑制成纤维细胞中的BRAF驱动血管生成反应的机制,并将阐明血管利基作为黑色素瘤细胞逃逸的保护地的作用。预计从这项工作中获得的知识将为临床克服BRAF抑制剂耐药性提供新的治疗策略。1
公共卫生相关性:尽管小分子BRAF抑制剂作为新的黑色素瘤疗法显示出巨大的前景,但它们的有效性受到获得性和内在耐药性的严重限制。该提案的目的是阐明宿主和肿瘤微环境对这两种耐药机制的作用机制。我们期望这项研究能为延缓和消除黑色素瘤耐药提供新的微环境导向策略,这些策略可以在未来的临床试验中进行评估。
项目成果
期刊论文数量(0)
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Keiran Smalley其他文献
Keiran Smalley的其他文献
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{{ truncateString('Keiran Smalley', 18)}}的其他基金
Defining and targeting the epigenetic programs involved in melanoma development
定义和瞄准参与黑色素瘤发展的表观遗传程序
- 批准号:
10543558 - 财政年份:2022
- 资助金额:
$ 34.65万 - 项目类别:
Defining and targeting the epigenetic programs involved in melanoma development
定义和瞄准参与黑色素瘤发展的表观遗传程序
- 批准号:
10354080 - 财政年份:2022
- 资助金额:
$ 34.65万 - 项目类别:
Targeting the suppressive immune microenvironment in leptomeningeal melanoma metastases
针对软脑膜黑色素瘤转移中的抑制性免疫微环境
- 批准号:
10456946 - 财政年份:2021
- 资助金额:
$ 34.65万 - 项目类别:
Targeting the suppressive immune microenvironment in leptomeningeal melanoma metastases
针对软脑膜黑色素瘤转移中的抑制性免疫微环境
- 批准号:
10290150 - 财政年份:2021
- 资助金额:
$ 34.65万 - 项目类别:
Abrogation of Therapeutic Escape Pathways in BRAF Mutant Melanoma
BRAF 突变黑色素瘤治疗逃逸途径的废除
- 批准号:
8556439 - 财政年份:2013
- 资助金额:
$ 34.65万 - 项目类别:
Microenvironment mediated drug resistance in melanoma.
微环境介导黑色素瘤耐药性。
- 批准号:
8301561 - 财政年份:2011
- 资助金额:
$ 34.65万 - 项目类别:
Microenvironment mediated drug resistance in melanoma.
微环境介导黑色素瘤耐药性。
- 批准号:
8479132 - 财政年份:2011
- 资助金额:
$ 34.65万 - 项目类别:
Microenvironment mediated drug resistance in melanoma.
微环境介导黑色素瘤耐药性。
- 批准号:
8851995 - 财政年份:2011
- 资助金额:
$ 34.65万 - 项目类别:
Microenvironment mediated drug resistance in melanoma.
微环境介导黑色素瘤耐药性。
- 批准号:
8666540 - 财政年份:2011
- 资助金额:
$ 34.65万 - 项目类别:
Abrogation of Therapeutic Escape Pathways in BRAF Mutant Melanoma
BRAF 突变黑色素瘤治疗逃逸途径的废除
- 批准号:
9134703 - 财政年份:
- 资助金额:
$ 34.65万 - 项目类别:
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