Exploiting Caveolae-Dependent Albumin Endocytosis to optimize Therapy in Pancreatic Cancer

利用小凹依赖的白蛋白内吞作用来优化胰腺癌的治疗

• 批准号: 10332467
• 负责人: Terence Marques Williams
• 金额: $ 12.42万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10332467
• 关键词: Exploiting; Caveolae; Dependent; Albumin; Endocytosis

 DESCRIPTION (provided by applicant): Pancreatic adenocarcinoma (PC) is a disease typified by resistance to therapy and poor outcomes. There is a pressing need to discover new therapies and determine whether existing therapies will be ineffective in certain patients. Recently, the addition of nab-paclitaxel (Abraxane(r)) to gemcitabine has been shown to improve response rates and survival in PC, at the expense of added toxicity. Nab-paclitaxel is an albumin-bound chemotherapeutic which has been hypothesized to enter the cell through caveolae/gp60-mediated albumin endocytosis. Caveolae are 50-100 nM membrane invaginations responsible for endocytosis, cholesterol homeostasis, and signal transduction. Caveolin-1 (Cav-1) is the principal structural component of caveolae, and genetic knockdown of Cav-1 ablates caveolae. Our preliminary data indicate that Cav-1 is over-expressed and associated with poor prognosis in PC, and confers oncogenic properties including migration, invasion, and resistance to therapy. Our data also suggest that Cav-1 expression is important for intracellular transport of albumin and nab-paclitaxel into PC cells. Thus, we hypothesize that Cav-1 levels regulate entry and can predict response to nab-paclitaxel. In addition, we seek to improve upon nab-paclitaxel by identifying other strategies which increase nab-paclitaxel efficacy and by testing novel albumin-conjugated chemotherapeutics. Our specific aims include: (1) To determine whether Cav-1 expression mediates albumin uptake and response to nab-paclitaxel; (2) To determine whether Cav-1 expression mediates response to novel albumin-conjugated chemotherapeutics; and (3) To test strategies to improve response to nab-paclitaxel. We will test whether Cav-1 levels affect response to nab-paclitaxel in a panel of PC cell lines through analysis of albumin and nab- paclitaxel uptake, cytotoxicity assays, and activation of apoptotic pathways. We will extend these studies in vivo to assess whether loss of Cav-1 alters response to nab-paclitaxel using patient-derived xenograft and autochthonous mouse models of PC. In addition, we will determine whether Cav-1 levels in tumor, stroma, and blood predict response to nab-paclitaxel in samples obtained from patients with PC receiving nab- paclitaxel. Furthermore, we will test novel albumin-chemotherapy conjugates that appear superior to nab- paclitaxel and determine whether Cav-1 levels also regulate their response. Lastly, we will test other strategies to increase Cav-1 expression in order to further sensitize cells to nab-paclitaxel If successful, these studies will establish that Cav-1 is important for albumin entry in PC tumor cells and dictates response to albumin- bound chemotherapies. Furthermore, these studies could allow personalization of therapy by predicting which tumors are likely to benefit from nab-paclitaxel, by stratifying therapy based on Cav-1 expression. Finally, these studies are designed to be the first to refine an existing therapy in PC through targeting of the Cav-1/caveolae-dependent albumin endocytic pathway.

 描述（由申请人提供）：胰腺癌（PC）是一种以治疗耐药和预后不良为特征的疾病，迫切需要发现新的疗法并确定现有疗法是否对某些患者无效。白蛋白结合型紫杉醇 (Abraxane(r)) 与吉西他滨相比，已被证明可以提高 PC 的缓解率和生存率，但代价是增加了白蛋白结合型紫杉醇的毒性。化疗药物通过小凹/gp60 介导的白蛋白内吞作用进入细胞，小凹是负责内吞作用、胆固醇稳态和信号转导的 50-100 nM 膜内陷，而 Caveolin-1 (Cav-1) 是主要结构成分。 Cav-1 的基因敲除消除了小凹，我们的初步数据表明 Cav-1 过度表达。与 PC 的不良预后相关，并具有致癌特性，包括迁移、侵袭和治疗耐药性。我们的数据还表明，Cav-1 表达对于白蛋白和白蛋白结合型紫杉醇向 PC 细胞的细胞内转运很重要。 Cav-1 水平调节进入并可以预测对白蛋白结合型紫杉醇的反应。此外，我们寻求通过确定提高白蛋白结合型紫杉醇疗效的其他策略并通过测试新的策略来改进白蛋白结合型紫杉醇。我们的具体目标包括：(1) 确定 Cav-1 表达是否介导白蛋白摄取和对白蛋白结合型紫杉醇的反应；(2) 确定 Cav-1 表达是否介导对新型白蛋白偶联化疗药物的反应；以及(3) 测试改善白蛋白结合型紫杉醇反应的策略 我们将通过分析白蛋白来测试 Cav-1 水平是否影响一组 PC 细胞系对白蛋白结合型紫杉醇的反应。我们将在体内扩展这些研究，以使用患者来源的异种移植和自体 PC 小鼠模型来评估 Cav-1 的缺失是否会改变对白蛋白结合型紫杉醇的反应。此外，我们将确定肿瘤、基质和血液中的 Cav-1 水平是否可以预测从接受白蛋白结合型紫杉醇的 PC 患者获得的样本中对白蛋白结合型紫杉醇的反应。此外，我们将测试优于白蛋白结合型紫杉醇的新型白蛋白化疗结合物，并确定 Cav-1 水平是否也调节其反应。最后，我们将测试增加 Cav-1 表达的其他策略，以进一步使细胞对白蛋白结合型紫杉醇敏感。 -紫杉醇 如果成功，这些研究将证实 Cav-1 对于白蛋白进入 PC 肿瘤细胞很重要，并决定对白蛋白结合化疗的反应。此外，这些研究可以通过预测实现个性化治疗。通过基于 Cav-1 表达的分层治疗，哪些肿瘤可能受益于白蛋白结合型紫杉醇 最后，这些研究旨在首次通过靶向 Cav-1/caveolae 依赖性白蛋白来完善 PC 的现有疗法。内吞途径。