Exploiting caveolae-dependent albumin endocytosis to optimize therapy in pancreatic cancer

利用小窝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：
9905249
负责人：
Terence Marques Williams
金额：
$ 5.72万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9905249
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 Endothelium 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 Structure 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 in vivo evaluation knock-down migration mouse model neoplastic cell novel novel marker novel therapeutics outcome forecast overexpression pancreatic cancer cells pancreatic cancer patients personalized medicine potential biomarker predicting response predictive marker response standard of care therapy resistant transcytosis treatment optimization tumor tumor microenvironment uptake

项目摘要

PROJECT ABSTRACT: 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®) 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.

项目摘要：胰腺癌（PC）是一种以治疗耐药和预后不良为特征的疾病。迫切需要发现新疗法并确定现有疗法是否在某些方面无效最近，在吉西他滨中添加白蛋白结合型紫杉醇 (Abraxane®) 已被证明可以改善患者的病情。 PC 中的缓解率和存活率，但代价是增加了白蛋白结合型紫杉醇的毒性。化疗药物已被利用通过小凹/gp60介导的白蛋白进入细胞小凹是负责内吞作用、胆固醇的 50-100 nM 膜内陷。 Caveolin-1 (Cav-1) 是小窝的主要结构成分，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、侵袭和我们的数据还表明 Cav-1 表达对于细胞内转运很重要。因此，我们认为 Cav-1 水平可以调节进入 PC 细胞。预测白蛋白结合型紫杉醇的反应此外，我们试图通过识别其他白蛋白结合型紫杉醇来改进白蛋白结合型紫杉醇。提高白蛋白结合型紫杉醇疗效的策略并通过测试新型白蛋白结合化疗药物。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反应 (2) 确定 Cav-1 表达是否介导对新型白蛋白缀合的反应化疗；以及（3）测试改善白蛋白结合型紫杉醇反应的策略。通过分析白蛋白和白蛋白结合型紫杉醇，1 水平影响一组 PC 细胞系中对白蛋白结合型紫杉醇的反应紫杉醇摄取、细胞毒性测定和细胞凋亡途径的激活我们将在以下领域扩展这些研究。使用患者来源的异种移植物体内评估 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、基质中的 Cav-1 水平。和血液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化疗结合物的新型白蛋白-化疗结合物。紫杉醇并确定 Cav-1 水平是否也调节其反应最后，我们将测试其他策略。如果成功，这些研究将增加 Cav-1 的表达，以进一步增强细胞对白蛋白结合型紫杉醇的敏感性。将确定 Cav-1 对于白蛋白进入 PC 肿瘤细胞很重要，并决定对白蛋白的反应此外，这些研究可以通过预测哪些疗法来实现个性化治疗。通过基于 Cav-1 表达的分层治疗，肿瘤可能受益于白蛋白结合型紫杉醇。研究旨在成为第一个通过针对 Cav-1/caveolae 来完善 PC 现有疗法的研究依赖的白蛋白内吞途径。