br G Draetta P Jones
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.
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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
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.
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 . Gemci-tabine has been a standard chemotherapeutic treatment for advanced PC since the late 1990s . 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) . 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 . 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).