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：
Keiran Smalley
金额：
$ 21.94万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
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：
https://reporter.nih.gov/project-details/8556439
关键词：
Address Adhesions Aftercare Apoptosis Apoptotic BCL2L11 gene BRAF gene Biological Markers Biopsy Bypass Cell Line Cell-Cell Adhesion Cell-Matrix Junction Chemicals Client Clinical Development Drug resistance Effectiveness Enrollment Evaluation Extracellular Matrix Fibroblasts Goals Growth Factor HSP 90 inhibition Heat shock proteins Heat-Shock Proteins 90 In Vitro Intrinsic drive MAP Kinase Gene MCL1 protein MEKs Maps Mediating Melanoma Cell Mitogen-Activated Protein Kinase Inhibitor N-Cadherin PI3K/AKT Pathway interactions Patients Pattern Phase I Clinical Trials Platelet-Derived Growth Factor Protein Tyrosine Kinase Proteins Proteomics Proto-Oncogene Proteins c-akt Receptor Protein-Tyrosine Kinases Relapse Resistance Role Signal Transduction Signaling Protein Skin Cancer Specimen System Systems Biology Testing Therapeutic Time Work adhesion receptor base design human FRAP1 protein improved in vivo inhibitor/antagonist innovation melanoma mutant network models novel novel therapeutics pre-clinical prevent pro-apoptotic protein protein degradation research study resistance mechanism response small molecule tumor

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.

我们的长期目标是制定治疗策略，以改善通过增强新的和现有的靶向疗法来传播黑色素瘤。尽管令人印象深刻在接受BRAF抑制剂治疗的BRAF突变性黑色素瘤患者中获得的反应，不可避免地发生。已经描述了许多潜在的电阻机制，其中大多数绕过突变的BRAF通过MAPK和PISK/AKT信号传导的重新激活。尽管目前的临床策略专注于与MEK或Pisk抑制剂结合使用BRAF抑制剂的发展黑色素瘤信号网络中许多节点的多次微妙信号改变可能会导致最终甚至对这些组合也有抵抗力。从概念上讲，我们认为适应性信号在大多数情况下，介导的耐药性都是“肿瘤中的”，这是由于重新布线而产生的黑色素瘤信号转导网络以及“宿主衍生”，由改变的生长因子介导基质成纤维细胞的分泌和细胞外基质。我们的工作假设是长期除了多个受体外，还可以将bf^f作为靶向，才能获得抗药性酪氨酸激酶（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BRAF抑制剂治疗逃脱有关的信号传导蛋白是热的客户休克蛋白（HSP）-90，我们表明HSP90的抑制作用可有效预防和克服体外和体内都有抗性。在此提案中，我们将使用创新的磷酸化蛋白质组学和化学基于蛋白质组学的系统生物学方法来定义驱动内在和获得了黑色素瘤对MAPK途径抑制的抗性（BRAF，MEK和BRAF+MEK）。我们将进一步研究成纤维细胞衍生的信号在重塑黑素瘤细胞的HSP-clientome中的作用并将确定这如何允许肿瘤逃脱MAPK抑制剂介导的细胞凋亡。治疗前后来自黑色素瘤患者接受BRAF和HSP90抑制剂组合的活检（Vemurafenib+XL888）将进行分析，以寻找与HSP客户蛋白降解的模式长期治疗反应。共同期望这些研究将对系统级别的观点提供有关如何黑色素瘤细胞抵抗MAPK途径抑制，并将提供新的范式来克服耐药性在黑色素瘤中。