Role of Cyr61/CCN1 in Pancreatic Cancer Progression and Therapy

Cyr61/CCN1 在胰腺癌进展和治疗中的作用

基本信息

批准号：
10339407
负责人：
SNIGDHA BANERJEE
金额：
--
依托单位：
KANSAS CITY VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-01 至 2024-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10339407
关键词：
3&apos Untranslated Regions Abraxane Acute Binding Sites Biological Availability Biological Markers Cell Line Chemopreventive Agent Clinical Trials Desmoplastic Dose Down-Regulation Drug Exposure Drug Kinetics Encapsulated Epithelial Female Fetal Diseases Future Goals Growth Human Hypoxia Imaging Techniques Immunocompetent In Vitro Inbred BALB C Mice Intravenous Investigational Drugs KRAS2 gene Kidney Lead Liver Luciferases Malignant Neoplasms Malignant neoplasm of pancreas Maximum Tolerated Dose Measures Mediating Mesenchymal Methods MicroRNAs Molecular Mus Neoplasm Metastasis Paclitaxel Pancreatic Ductal Adenocarcinoma Phenotype Plasma Plasmids Play Primary Neoplasm Production Property Proteins Regulation Renal clearance function Reporter Research Resistance Role Route Sampling Signal Pathway Signal Transduction Site Source Spleen Standardization Techniques Testing Time Tissues Toxic effect Treatment Efficacy Tumor Suppressor Proteins Ultrasonography Veterans Xenograft procedure Zoledronic Acid base bone cancer cell cancer therapy cell growth cell motility chemotherapy gemcitabine genetically modified cells improved in vivo in vivo imaging intravenous administration male migration mortality mouse model multidisciplinary mutant nanocapsule nanocarrier nanodrug novel strategies novel therapeutic intervention overexpression pancreatic cancer cells pancreatic ductal adenocarcinoma cell pancreatic ductal adenocarcinoma model pancreatic neoplasm patient derived xenograft model prognostic response targeted treatment tissue biomarkers tissue culture tumor tumor growth tumor progression uptake

项目摘要

Pancreatic ductal adenocarcinoma (PDAC) remains one of the leading sources of cancer mortality worldwide, including US Veterans. An initial response to chemotherapy, such as Gemcitabine (GEM) is often followed by emergent resistance reflecting an urgent need for targeted therapies. Our studies have found that CYR61 is a druggable PDAC driver, and it can be suppressed by Zoledronic acid (ZA) under tissue culture conditions. Regrettably, the weak availability in the target tissue limits the therapeutic efficacy of ZA. Thus, the goal of this proposal is to evaluate a new approach for an iRGD-mediated-hypoxic/pH-responsive nanocarriers (ZA-iPRNCs) based therapy, which can efficiently release ZA from the nano-capsule exclusively in the hypoxic microenvironment of PDAC. In our in vitro and in vivo preliminary studies, we have established the feasibility of the proposed method. We have shown that like free-ZA, CYR61 expression can be blocked significantly by ZA- iPRNCs in different PDAC cell lines. We have also obtained results indicating that after intravenous delivery to tumor-bearing mice, ZA-iPRNCs lead to robust tumor uptake detectable by in vivo imaging and, importantly, results in suppression of CYR61 expression and tumor growth. Building on these exciting preliminary findings, we now propose to unravel the mechanism of regulation of CYR61 by ZA, and determine whether ZA, via blocking CYR61, inhibits PDAC growth and metastatic progression as well as makes cancer cells sensitive to GEM using genetically engineered cell lines and mouse models. Further, we will also explore an additive impact of nab-paclitaxel (Abraxane, NPac) on GEM sensitivity in tumor-bearing mice treated with ZA-iPRNCs, GEM, and NPac together. To accomplish these goals, we propose three aims. In Aim 1, we will dissect the mechanism of regulation of CYR61 expression in PDAC cells by ZA. In Aim 2, we will determine the maximum tolerated dose (MTD) and bioavailability of ZA using immunocompetent mice. Lastly, in Aim 3, we will evaluate whether nano carrier-based ZA therapy alone or in a combination of ZA-iPRNCs, GEM, and NPac leads to improved tumor control and mouse survival in KPC and PDX mouse models. To achieve these aims, we have standardized a non-invasive ultrasound imaging technique that reveals the various steps of tumor progression in mouse models. With the help of these techniques and the unique collaborative expertise of the multidisciplinary team, we will establish a new therapeutic approach for future clinical trials.

胰腺导管腺癌（PDAC）仍然是全球癌症死亡率的主要来源之一，包括美国退伍军人。对吉西他滨 (GEM) 等化疗产生初步反应后，通常会出现以下反应：出现的耐药性反映出对靶向治疗的迫切需要。我们的研究发现CYR61是一个可药物化的 PDAC 驱动器，在组织培养条件下可被唑来膦酸 (ZA) 抑制。遗憾的是，ZA 在靶组织中的有效性较弱限制了其治疗效果。因此，本次活动的目标提案是评估 iRGD 介导的缺氧/pH 响应纳米载体 (ZA-iPRNC) 的新方法基于治疗，可以仅在缺氧的情况下从纳米胶囊中有效地释放ZA PDAC的微环境。在我们的体外和体内初步研究中，我们已经确定了以下方法的可行性：所提出的方法。我们已经证明，与游离 ZA 一样，CYR61 的表达可以被 ZA-显着阻断。不同 PDAC 细胞系中的 iPRNC。我们还获得的结果表明，静脉注射后荷瘤小鼠中，ZA-iPRNC 导致强大的肿瘤摄取，可通过体内成像检测到，重要的是，导致 CYR61 表达和肿瘤生长的抑制。基于这些令人兴奋的初步发现，我们现在建议阐明ZA对CYR61的调节机制，并确定ZA是否通过阻断 CYR61，抑制 PDAC 生长和转移进展，并使癌细胞对 GEM 使用基因工程细胞系和小鼠模型。此外，我们还将探索附加影响白蛋白结合型紫杉醇 (Abraxane, NPac) 对接受 ZA-iPRNC、GEM 治疗的荷瘤小鼠的 GEM 敏感性的影响和 NPAC 一起。为了实现这些目标，我们提出三个目标。在目标 1 中，我们将剖析该机制 ZA 对 PDAC 细胞中 CYR61 表达的调节。在目标 2 中，我们将确定最大容忍度使用免疫活性小鼠测定 ZA 的剂量 (MTD) 和生物利用度。最后，在目标 3 中，我们将评估是否基于纳米载体的 ZA 疗法单独或与 ZA-iPRNC、GEM 和 NPac 组合使用可改善 KPC 和 PDX 小鼠模型中的肿瘤控制和小鼠存活。为了实现这些目标，我们制定了标准化一种非侵入性超声成像技术，揭示小鼠肿瘤进展的各个步骤模型。借助这些技术和多学科团队独特的协作专业知识，我们将为未来的临床试验建立一种新的治疗方法。