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.
Given the limited efficacy of available therapies in PDAC, a significant focus in PDAC research has been on developing targeted therapies to interfere with the fetal disease effectively. In the proposed research application, we will utilize an iRGD-mediated-hypoxic/pH-responsive nanocarriers (iPRNCs) based therapy. The targeted nano drug will release ZA and uniquely target pancreatic tumors, their microenvironments, and metastatic sites through inhibiting the CYR61-signaling pathway. To that end, the findings of these studies will help in interpreting the results for potential clinical trials of iPRNC-ZA therapy for PDAC.
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