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

基本信息

批准号：
9249514
负责人：
Terence Marques Williams
金额：
$ 39.72万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9249514
关键词：
Ablation Abraxane Adenocarcinoma Cell Affect Albumins Apoptotic Biological Assay Blood Caveolae Cell Line Cells Cholesterol Homeostasis Clinical Clinical Trials Cremophor Data Disease Disseminated Malignant Neoplasm Down-Regulation Endocytosis Genetic Goals Growth Human Impairment In Vitro Intracellular Transport KRAS2 gene Malignant Neoplasms Malignant neoplasm of pancreas Mediating Membrane Metastatic Pancreatic Adenocarcinoma Methods Modeling Mutation Neoplasm Metastasis Normal tissue morphology Oncogenic Outcome Paclitaxel Pancreatic Adenocarcinoma Pathway interactions Patients Pharmaceutical Preparations Property Proteins Radiation Research Role Sampling Schedule Serum Signal Transduction Solvents Testing Toxic effect Treatment Efficacy Treatment outcome Tumor Tissue Ursidae Family Xenograft procedure base biomarker-driven cancer type caveolin 1 chemotherapy clinical translation clinically translatable comparative efficacy cytotoxicity design efficacy testing gemcitabine improved in vitro testing in vivo knock-down migration mouse model neoplastic cell novel novel marker novel therapeutics outcome forecast overexpression pancreatic cancer cells personalized medicine potential biomarker predicting response predictive marker public health relevance response standard of care therapy resistant transcytosis tumor tumor microenvironment uptake

项目摘要

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（由适用提供）：胰腺腺癌（PC）是一种疾病，其疾病是对治疗和不良结局的抗性。迫切需要发现新的疗法，并确定某些患者现有疗法是否无效。最近，已证明将NAB-甲前烷（Abraxane（R））添加到吉西他滨向吉西他滨添加可提高PC中的反应率和生存率，而牺牲毒性为代价。 NAB-PACLITAXEL是一种白蛋白结合的化学治疗性，已被认为可以通过Caveolae/GP60介导的白蛋白内吞作用进入细胞。小窝是50-100 nm的膜起伏，负责内吞作用，胆固醇稳态和信号转导。 Caveolin-1（Cav-1）是小窝的主要结构成分，也是Cav-1消融口腔的遗传敲低。我们的初步数据表明，CAV-1过表达，并且与PC的预后不良有关，并且赋予了包括迁移，入侵和对治疗的抗性的致癌特性。我们的数据还表明，CAV-1表达对于将白蛋白和NAB-甲酰胺二昔二奈向PC细胞的细胞内转运很重要。这是我们假设CAV-1水平调节进入的水平，并可以预测对NAB-PACLITAXEL的反应。此外，我们试图通过鉴定提高NAB-甲氟甲酰胺有效性并测试新型专辑偶联化学疗法的其他策略来改善NAB-PACLITAXEL。我们的具体目的包括：（1）确定Cav-1表达中值白蛋白的吸收和对NAB-甲曲奈的反应；（2）确定CAV-1表达中值是否反应新型专辑偶联化学治疗剂；（3）测试策略以改善对NAB-PACLITAXEL的反应。我们将通过分析白蛋白和NAB-甲氟甘列赛摄取，细胞毒性测定和凋亡途径的激活来测试CAV-1水平是否会影响PC细胞系中对NAB-甲氟己二酰基的反应。我们将在体内扩展这些研究，以评估使用PC的患者衍生的Xenogroticon和自摄影小鼠模型来评估CAV-1的损失是否会改变对NAB-甲酰胺的反应。此外，我们将确定在接受接受NAB-甲酰胺的PC患者获得的样品中，肿瘤，基质和血液中的CAV-1水平是否可以预测对NAB-列甲酰胺的反应。此外，我们将测试新型的专辑化学化学疗法结合物，这些结合物看起来优于NAB-甲酰胺，并确定CAV-1水平是否还调节其反应。最后，我们将测试其他策略以增加CAV-1表达，以便将敏感的细胞进一步为NAB-甲列酰胺，如果成功，这些研究将确定CAV-1对于PC肿瘤细胞中的白蛋白进入至关重要，并决定了对专辑结合化学疗法的反应。此外，这些研究可以通过根据CAV-1表达来分层治疗，通过预测哪些肿瘤可能受益于NAB-甲氟乙酰赛，可以通过预测哪些肿瘤受益。最后，这些研究被设计为第一个通过靶向CAV-1/Caveolae依赖性白蛋白内吞途径来完善PC中现有疗法的研究。