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：
10388426
负责人：
Terence Marques Williams
金额：
$ 7.73万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
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 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10388426
关键词：
Ablation Abraxane Adenocarcinoma Cell Affect Albumins Apoptotic Biological Assay Blood Caveolae Cell Line Cells Chemotherapy and/or radiation 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 Prognosis Property Proteins Radiation Research Role Sampling Schedule Serum Signal Transduction Solvents Structure Testing Toxic effect Treatment Efficacy Treatment outcome Tumor Tissue Ursidae Family 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 overexpression pancreatic cancer cells pancreatic cancer patients patient derived xenograft model personalized medicine potential biomarker predicting response predictive marker public health relevance response standard of care therapy resistant transcytosis treatment optimization 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。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

MicroRNA molecular profiling identifies potential signaling pathways conferring resistance to chemoradiation in locally-advanced rectal adenocarcinoma.

MicroRNA 分子分析可识别局部晚期直肠腺癌对放化疗产生耐药性的潜在信号通路。

DOI：
发表时间：
2018-06-22
期刊：
影响因子：
0
作者：
Pettit, Cory;Webb, Amy;Walston, Steve;Chatterjee, Moumita;Chen, Wei;Frankel, Wendy;Croce, Carlo;Williams, Terence M
通讯作者：
Williams, Terence M

Prognostic value of microRNA expression levels in pancreatic adenocarcinoma: a review of the literature.

胰腺癌中 microRNA 表达水平的预后价值：文献综述。

DOI：
发表时间：
2017-09-22
期刊：
影响因子：
0
作者：
Wald, Patrick;Liu, X Shawn;Pettit, Cory;Dillhoff, Mary;Manilchuk, Andrei;Schmidt, Carl;Wuthrick, Evan;Chen, Wei;Williams, Terence M
通讯作者：
Williams, Terence M

Identifying Clinical Factors Which Predict for Early Failure Patterns Following Resection for Pancreatic Adenocarcinoma in Patients Who Received Adjuvant Chemotherapy Without Chemoradiation.

确定预测接受辅助化疗但未放化疗的患者胰腺腺癌切除后早期失败模式的临床因素。

DOI：
发表时间：
2018
期刊：
影响因子：
0
作者：
Walston, Steve;Salloum, Joseph;Grieco, Carmine;Wuthrick, Evan;Diaz, Dayssy A;Barney, Christian;Manilchuk, Andrei;Schmidt, Carl;Dillhoff, Mary;Pawlik, Timothy M;Williams, Terence M
通讯作者：
Williams, Terence M

Caveolae-Mediated Endocytosis Is Critical for Albumin Cellular Uptake and Response to Albumin-Bound Chemotherapy.

小凹介导的内吞作用对于白蛋白细胞摄取和对白蛋白结合化疗的反应至关重要。

DOI：
10.1158/0008-5472.can-17-0604
发表时间：
2017-11-01
期刊：
Cancer research
影响因子：
11.2
作者：
Chatterjee M;Ben-Josef E;Robb R;Vedaie M;Seum S;Thirumoorthy K;Palanichamy K;Harbrecht M;Chakravarti A;Williams TM
通讯作者：
Williams TM

The Impact of Novel Radiation Treatment Techniques on Toxicity and Clinical Outcomes In Rectal Cancer.

新型放射治疗技术对直肠癌毒性和临床结果的影响。