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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：
9106967
负责人：
Terence Marques Williams
金额：
$ 40.09万
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/9106967
关键词：
Ablation Abraxane Adenocarcinoma Cell Affect Albumins Apoptotic Binding 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 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 Research Design Role Sampling Schedule Serum Signal Transduction Solvents Survival Rate Testing Toxic effect Translations Treatment Efficacy Treatment outcome Tumor Tissue Ursidae Family Xenograft procedure base biomarker-driven cancer type caveolin 1 chemotherapy comparative efficacy cytotoxicity efficacy testing gemcitabine improved in vitro testing in vivo knock-down migration mouse model neoplastic cell novel novel marker novel therapeutics outcome forecast pancreatic cancer cells 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.