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  • br G Draetta P Jones

    2020-08-07


    G. Draetta, P. Jones, C. Toniatti, M.E.D. Francesco, J.R. Marszalek, A novel OXPHOS inhibitor which selectively kill tumors with metabolic vulnerabilities, The 106th Annual Meeting of the American Association for Cancer Research, AACR, Philadelphia, PA, 2015.
    Contents lists available at ScienceDirect
    Cancer Letters
    journal homepage: www.elsevier.com/locate/canlet
    Original Articles
    Bioengineered miRNA-1291 prodrug therapy in pancreatic cancer sybr safe and T patient-derived xenograft mouse models
    Mei-Juan Tua, Pui Yan Hoa, Qian-Yu Zhanga, Chao Jiana, Jing-Xin Qiub, Edward J. Kimc, Richard J. Boldd, Frank J. Gonzaleze, Huichang Bif, Ai-Ming Yua,∗ a Department of Biochemistry & Molecular Medicine, UC Davis School of Medicine, Sacramento, CA, 95817, USA
    c Division of Hematology and Oncology, UC Davis School of Medicine, Sacramento, CA, 95817, USA
    d Department of Surgery, UC Davis School of Medicine, Sacramento, CA, 95817, USA
    e Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
    f School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
    Keywords:
    Pancreatic cancer
    PDX model
    ARID3B
    Gemcitabine plus nab-paclitaxel 
    Our recent studies have revealed that microRNA-1291 (miR-1291) is downregulated in pancreatic cancer (PC) specimens and restoration of miR-1291 inhibits tumorigenesis of PC cells. This study is to assess the efficacy and underlying mechanism of our bioengineered miR-1291 prodrug monotherapy and combined treatment with chemotherapy. AT-rich interacting domain protein 3B (ARID3B) was verified as a new target for miR-1291, and miR-1291 prodrug was processed to mature miR-1291 in PC cells which surprisingly upregulated ARID3B mRNA and protein levels. Co-administration of miR-1291 with gemcitabine plus nab-paclitaxel (Gem-nP) largely in-creased the levels of apoptosis, DNA damage and mitotic arrest in PC cells, compared to mono-drug treatment. Consequently, miR-1291 prodrug improved cell sensitivity to Gem-nP. Furthermore, systemic administration of in vivo-jetPEI-formulated miR-1291 prodrug suppressed tumor growth in both PANC-1 xenograft and PC patients derived xenograft (PDX) mouse models to comparable degrees as Gem-nP alone, while combination treatment reduced tumor growth more ubiquitously and to the greatest degrees (70–90%), compared to monotherapy. All treatments were well tolerated in mice. In conclusion, biologic miR-1291 prodrug has therapeutic potential as a monotherapy for PC, and a sensitizing agent to chemotherapy.
    1. Introduction
    Pancreatic cancer (PC) is one of the most lethal malignancies with a 5-year survival of less than 8% [1,2]. Less than 20% of PC patients are diagnosed with surgically resectable disease and are potentially cur-able. The remaining large majority of PC patients are diagnosed with advanced disease that is either unresectable or metastatic [3]. Gemci-tabine has been a standard chemotherapeutic treatment for advanced PC since the late 1990s [4]. After more than a decade of active in-vestigation, the first clinical improvement to gemcitabine-based treat-ment was seen with the addition of paclitaxel albumin-stabilized na-noparticle (nab-paclitaxel) formulation (Gem-nP) which increased
    overall median survival (8.5 months) compared to gemcitabine mono-therapy (6.7 months) [5]. Compared to most other solid tumors, ad-vance in the treatment of PC has been slow, thus more effective treat-ment strategies with minimal toxicity are urgently needed for PC [6–9].
    MicroRNAs (miRNAs) have been revealed as a family of noncoding RNAs (ncRNA) in the control of tumor initiation and progression [10,11]. Furthermore, multiple miRNAs display tissue -specific aberrant expression in cancer development, suggesting the potential of devel-oping miRNA based anticancer therapies besides serving as diagnostic or prognostic markers [12,13] including those for PC [14–16]. Re-cently, we have identified that miR-1291 is significantly downregulated in PC tissues compared with normal pancreatic tissues [17]. Our studies
    Abbreviations: miR-1291, microRNA-1291; PC, pancreatic cancer; ARID3B, AT-rich interacting domain protein 3B; Gem-nP, gemcitabine plus nab-paclitaxel; PDX, patient-derived xenograft; miRNAs, microRNAs; ncRNA, noncoding RNAs; MRP1, multidrug resistance-associated protein 1; GLUT1, glucose transporter protein type 1; MUC1, mucin 1; MSA, sephadex aptamer tagged methionyl-tRNA; MREs, miRNA response elements; c-caspase-3/7, cleaved caspase-3/7; FPLC, fast protein liquid chromatography
    ∗ Corresponding author. Department of Biochemistry & Molecular Medicine, UC Davis School of Medicine, 2700 Stockton Blvd., Suite 2132, Sacramento, CA, 95817, USA.
    Fig. 1. MiR-1291 targets ARID3B and upregulates its expression in human pancreatic cancer cells. (A) Computational analysis identified four putative MRE sites for miR-1291 within the 3’UTR of ARID3B mRNA. Underlined is the seed sequence of miR-1291. (B) Dual luciferase reporter assay indicated that ARID3B 3’UTR luciferase activities were increased about 50% in AsPC-1 cells treated with MSA/mir-1291, as compared to controls. (C) qPCR analyses revealed that MSA/mir-1291 was selectively processed to mature miR-1291 in PANC-1 and AsPC-1 cells, and subsequently upregulated ARID3B mRNA levels (D). Values are mean ± SD (N = 3).