Role of Cyr61/CCN1 in Pancreatic Cancer Progression and Therapy

胰腺导管腺癌(PDAC)仍然是全球癌症死亡的主要来源之一， 包括美国退伍军人。对化疗的初始反应，如吉西他滨(GEM)，通常之后是 紧急耐药性反映了对靶向治疗的迫切需要。我们的研究发现，CYR61是一种 在组织培养条件下，它可被唑来膦酸(ZA)抑制。 遗憾的是，ZA在靶组织中的低利用度限制了ZA的治疗效果。因此，这一目标是 建议评估IRGD介导的缺氧/pH响应型纳米载体(ZA-iPRNC)的一种新方法 基础疗法，可有效地从纳米胶囊中释放ZA，仅在缺氧时 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 所提出的方法。我们已经证明，与Free-Za一样，Za-Za也能显著阻断CYR61的表达。 不同PDAC细胞系中的iPRNC。我们还获得了结果表明，静脉给药后 荷瘤小鼠，ZA-iPRNC可通过体内成像检测到强大的肿瘤摄取，重要的是， 结果抑制了CyR61的表达和肿瘤的生长。在这些令人兴奋的初步发现的基础上， 我们现在建议解开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 使用基因工程细胞系和小鼠模型的GEM。此外，我们还将探索一个附加影响 NaB-紫杉醇(Abraxane，NPAc)对ZA-iPRNCs，GEM， 和NPAC在一起。为了实现这些目标，我们提出了三个目标。在目标1中，我们将剖析其机制 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 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 基于纳米载体的ZA治疗单独或联合ZA-iPRNCs、GEM和NPAC可导致改善 KPC和PDX小鼠模型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 模特们。在这些技术和多学科团队独特的协作专业知识的帮助下， 我们将为未来的临床试验建立一种新的治疗方法。

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.