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

• 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
• 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' 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

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。对化学疗法的初步反应，例如吉西他滨（GEM） 紧急抗性反映了迫切需要靶向疗法。我们的研究发现CYR61是 可吸毒的PDAC驱动器，在组织培养条件下可以通过唑来膦酸（ZA）抑制它。 遗憾的是，目标组织的较弱可用性限制了ZA的治疗功效。因此，目标的目标 建议是评估IRGD介导的催眠/pH响应性纳米载体（ZA-IPRNC）的新方法 基于基于缺氧的纳米胶囊可以有效地从纳米胶囊中释放ZA的疗法 PDAC的微环境。在我们的体外和体内初步研究中，我们确定了 提出的方法。我们已经表明，像自由ZA一样，CYR61表达可以被ZA-显着阻止 IPRNC在不同的PDAC细胞系中。我们还获得了结果，表明静脉注射后 具有肿瘤的小鼠，ZA-IPRNC会导致可通过体内成像检测到可观的肿瘤摄取，并且重要的是 导致CYR61表达和肿瘤生长的抑制。以这些令人兴奋的初步发现为基础 现在，我们建议通过ZA阐明CYR61调节的机制，并确定ZA是否是否通过 阻止CYR61，抑制PDAC的生长和转移性进展，并使癌细胞敏感 使用基因设计的细胞系和鼠标模型的GEM。此外，我们还将探索添加剂的影响 NAB-甲酰胺（Abraxane，NPAC）在用ZA-IPRNC，GEM，GEM，GEM，GEM， 和NPAC在一起。为了实现这些目标，我们提出了三个目标。在AIM 1中，我们将剖析机制 通过ZA调节PDAC细胞中CYR61表达的调节。在AIM 2中，我们将确定最大耐受性 使用免疫能力小鼠ZA的剂量（MTD）和生物利用度。最后，在AIM 3中，我们将评估是否 单独或基于ZA-IPRNC，GEM和NPAC的纳米载体ZA治疗可改善 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，我们已经标准化 一种非侵入性超声成像技术，揭示了小鼠肿瘤进展的各个步骤 型号。借助这些技术以及多学科团队的独特协作专业知识， 我们将为将来的临床试验建立一种新的治疗方法。