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
• 负责人: Keiran Smalley
• 金额: $ 21.37万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9134703
• 关键词: Address; Adhesions; Aftercare; Apoptosis; Apoptotic; BCL2L11 gene; BRAF gene; Biopsy; Bypass; Cell Line; Cell-Cell Adhesion; Cell-Matrix Junction; Chemicals; Client; Clinical; Development; Drug resistance; Effectiveness; Enrollment; Evaluation; Extracellular Matrix; FRAP1 gene; Fibroblasts; Goals; Growth; HSP 90 inhibition; Heat shock proteins; Heat-Shock Proteins 90; In Vitro; Intrinsic drive; MAP Kinase Gene; 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; improved; in vivo; inhibitor/antagonist; innovation; melanoma; mutant; network models; novel; novel therapeutics; phase I trial; phosphoproteomics; pre-clinical; prevent; pro-apoptotic protein; protein degradation; research study; resistance mechanism; response; response biomarker; small molecule inhibitor; targeted treatment; treatment response; tumor

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化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。