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
基本信息
- 批准号:8556439
- 负责人:
- 金额:$ 21.94万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-09-20 至 2018-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdhesionsAftercareApoptosisApoptoticBCL2L11 geneBRAF geneBiological MarkersBiopsyBypassCell LineCell-Cell AdhesionCell-Matrix JunctionChemicalsClientClinicalDevelopmentDrug resistanceEffectivenessEnrollmentEvaluationExtracellular MatrixFibroblastsGoalsGrowth FactorHSP 90 inhibitionHeat shock proteinsHeat-Shock Proteins 90In VitroIntrinsic driveMAP Kinase GeneMCL1 proteinMEKsMapsMediatingMelanoma CellMitogen-Activated Protein Kinase InhibitorN-CadherinPI3K/AKTPathway interactionsPatientsPatternPhase I Clinical TrialsPlatelet-Derived Growth FactorProtein Tyrosine KinaseProteinsProteomicsProto-Oncogene Proteins c-aktReceptor Protein-Tyrosine KinasesRelapseResistanceRoleSignal TransductionSignaling ProteinSkin CancerSpecimenSystemSystems BiologyTestingTherapeuticTimeWorkadhesion receptorbasedesignhuman FRAP1 proteinimprovedin vivoinhibitor/antagonistinnovationmelanomamutantnetwork modelsnovelnovel therapeuticspre-clinicalpreventpro-apoptotic proteinprotein degradationresearch studyresistance mechanismresponsesmall moleculetumor
项目摘要
Our long-term goal is to develop therapeutic strategies that improve the survival of patients with
disseminated melanoma by potentiating new and existing targeted therapies. Despite the impressive
responses achieved in BRAF mutant melanoma patients treated with BRAF inhibitors, resistance inevitably
occurs. A number of potential resistance mechanisms have been described, the majority of which bypass
mutant BRAF through the reactivation of MAPK and PISK/AKT signaling. Although current clinical strategies
are focused upon the use of BRAF inhibitors in conjunction with MEK or PISK inhibitors, the development of
multiple, subtle signaling alterations at many nodes within the melanoma signaling network is likely to result
in eventual resistance even to these combinations. Conceptually, we believe that the adaptive signals that
mediate resistance in the majority of cases are both "tumor-intrinsic", resulting from the rewiring of the
melanoma signal transduction network, as well as "host-derived", mediated by altered growth factor
secretion and extracellular matrix from stromal fibroblasts. Our working hypothesis is that long-term
abrogation of resistance will only be achieved if BF^F can be targeted in addition to multiple receptor
tyrosine kinase (RTKs) and cell/matrix adhesion signals. Our preliminary studies suggest that most if not all
of the signaling proteins implicated thus far in the escape from BRAF inhibitor therapy are clients of heat
shock protein (HSP)-90, and we showed that inhibition of HSP90 was effective at preventing and overcoming
resistance both in vitro and in vivo. In this proposal, we will use innovative phosphoproteomic- and chemical
proteomic-based systems biology approaches to define the HSP "clientome" that drives intrinsic and
acquired resistance of melanomas to MAPK pathway inhibition (BRAF, MEK and BRAF+MEK). We will
further investigate the role of fibroblast-derived signals in remodeling the HSP-clientome of melanoma cells
and will determine how this allows the tumor to escape MAPK inhibitor-mediated apoptosis. Pre- and post-treatment
biopsies from melanoma patients receiving a BRAF and HSP90 inhibitor combination
(vemurafenib+XL888) will be analyzed to look for patterns of HSP client protein degradation associated with
long-term therapeutic response. Together, these studies are expected to give a systems level view of how
melanoma cells resist MAPK pathway inhibition and will provide new paradigms to overcome drug resistance
in melanoma.
我们的长期目标是开发提高患者生存率的治疗策略
通过加强新的和现有的靶向治疗来抑制播散性黑色素瘤。尽管令人印象深刻
使用 BRAF 抑制剂治疗的 BRAF 突变黑色素瘤患者取得的反应,耐药性不可避免
发生。已经描述了许多潜在的阻力机制,其中大多数绕过
通过重新激活 MAPK 和 PISK/AKT 信号传导来抑制突变 BRAF。尽管目前的临床策略
专注于将 BRAF 抑制剂与 MEK 或 PISK 抑制剂结合使用,开发
黑色素瘤信号网络内许多节点的多重、微妙的信号改变可能会导致
最终甚至对这些组合产生抵制。从概念上讲,我们认为自适应信号
在大多数情况下,介导的耐药性都是“肿瘤固有的”,是由肿瘤细胞的重新布线造成的。
黑色素瘤信号转导网络,以及“宿主衍生的”,由改变的生长因子介导
基质成纤维细胞的分泌物和细胞外基质。我们的工作假设是长期
只有在多受体之外还能够靶向 BF^F 才能消除耐药性
酪氨酸激酶 (RTK) 和细胞/基质粘附信号。我们的初步研究表明,大多数(如果不是全部)
迄今为止,与逃避 BRAF 抑制剂治疗有关的信号蛋白是热的客户
休克蛋白(HSP)-90,我们发现抑制 HSP90 可以有效预防和克服
体外和体内的耐药性。在本提案中,我们将使用创新的磷酸蛋白质组学和化学方法
基于蛋白质组学的系统生物学方法来定义驱动内在和
黑色素瘤对 MAPK 通路抑制(BRAF、MEK 和 BRAF+MEK)的获得性耐药。我们将
进一步研究成纤维细胞衍生信号在重塑黑色素瘤细胞 HSP 客户组中的作用
并将确定这如何让肿瘤逃避 MAPK 抑制剂介导的细胞凋亡。治疗前和治疗后
接受 BRAF 和 HSP90 抑制剂组合治疗的黑色素瘤患者的活检
(vemurafenib+XL888) 将被分析以寻找与相关的 HSP 客户蛋白降解模式
长期治疗反应。总之,这些研究预计将给出一个系统层面的观点:
黑色素瘤细胞抵抗MAPK通路抑制,将为克服耐药性提供新范例
在黑色素瘤中。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Keiran Smalley其他文献
Keiran Smalley的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
$ 21.94万 - 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:
$ 21.94万 - 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:
$ 21.94万 - 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:
$ 21.94万 - 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:
$ 21.94万 - 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:
$ 21.94万 - 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:
$ 21.94万 - 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:
$ 21.94万 - 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:
8163854 - 财政年份:2011
- 资助金额:
$ 21.94万 - 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:
$ 21.94万 - 项目类别:
相似国自然基金
人胎盘水凝胶类器官贴片重建子宫内膜对重度宫腔粘连的作用及机制研究
- 批准号:
- 批准年份:2023
- 资助金额:49 万元
- 项目类别:
促细胞外囊泡分泌的绒毛膜纳米纤维仿生培养体系的构建及其在宫腔粘连修复中的应用研究
- 批准号:32301204
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
负载羟基喜树碱的双层静电纺纳米纤维膜抑制肌腱粘连组织增生的作用和相关机制研究
- 批准号:82302691
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
ROS清除型动态粘附水凝胶的制备及其在声带粘连防治中的作用与机制研究
- 批准号:82301292
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
基于“胞宫藏泻”理论探讨补肾养营活血方和HuMSCs调节ERS介导的细胞焦亡重塑粘连宫腔内膜容受态的研究
- 批准号:82305302
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
相似海外基金
Endothelial-Leukocyte Adhesion in CAR T Cell Treatment Associated Neurotoxicity
CAR T 细胞治疗相关神经毒性中的内皮-白细胞粘附
- 批准号:
10735681 - 财政年份:2023
- 资助金额:
$ 21.94万 - 项目类别:
Extracellular Vesicle Therapy for Diabetic Retinopathy
细胞外囊泡治疗糖尿病视网膜病变
- 批准号:
10723000 - 财政年份:2023
- 资助金额:
$ 21.94万 - 项目类别:
Treatment of Inflammatory Complications of Viral Pneumonia
病毒性肺炎炎症并发症的治疗
- 批准号:
10383991 - 财政年份:2022
- 资助金额:
$ 21.94万 - 项目类别:
PET Imaging of Vaso-Occlussive Crisis in Sickle Cell Disease
镰状细胞病血管闭塞危象的 PET 成像
- 批准号:
10366801 - 财政年份:2022
- 资助金额:
$ 21.94万 - 项目类别: