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    Cancer letters. 2017 Aug 29. pii: S0304-3835(17)30515-3. doi: 10.1016/j.canlet.2017.08.028
    A novel chemoradiation targeting stem and nonstem pancreatic cancer cells by repurposing Disulfiram.
    Cong J1,  Wang Y2,  Zhang X3,  Zhang N4,  Liu L5,  Soukup K6,  Michelakos T7,  Hong T8,  DeLeo A9,  Cai L10,  Sabbatino F11,  Ferrone S12,  Lee H13,  Levina V14,  Fuchs B15,  Tanabe K16,  Lillemoe K17,  Ferrone C18,  Wang X19
    Author information
    1Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
    2Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
    3Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
    4Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
    5Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
    6Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA; St. Anna Kinderkrebsforschung, Children's Cancer Research Institute, Vienna, Austria.
    7Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
    8Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
    9University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA; Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA; St. Anna Kinderkrebsforschung, Children's Cancer Research Institute, Vienna, Austria.
    10Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
    11Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
    12Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Orthopedic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
    13Department of Biostatistics Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
    14University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA.
    15Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
    16Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
    17Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
    18Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
    19Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: xwang30@mgh.harvard.edu.
    Abstract

    Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of 6% and is projected to be the second leading cause of cancer death by 2030, underscoring the urgency to develop new strategies to improve current therapeutic modalities for PDAC. Targeting pancreatic cancer stem cells (PCSCs), which are resistant to radiation and chemotherapy, is a promising strategy. A novel approach which can be readily clinically translated is to repurpose disulfiram (DSF), a drug for treating alcoholism, to target PCSCs. Chemoradiation or the combination of chemotherapy agents FOLFIRINOX, currently standard care for PDAC, can increase stemness in some established or primary PDAC cell lines. However, DSF in the presence of exogenously or endogenously supplied copper (Cu), when combined with chemotherapy or chemoradiation, targets both PCSCs and nonstem PDAC cells. Previously, we demonstrated that DSF/Cu effectively targets breast cancer stem cells in the context of fractionated radiation (FIR) by inhibiting the NF-κB-stemness gene pathway. Therefore, the hypothesis that PCSCs can be effectively targeted by incorporating DSF/Cu into the standard chemoradiation regimen consisting of 5-FU and FIR was investigated and found to be effective in vitro in targeting PCSCs, identified as either ALDH(bright,) CD24+/CD44+/ESA+ or sphere-forming cells, as well as nonstem PDAC cells. In vivo, the combination of IR+5-FU+DSF/Cu was more effective (72.46 %) than either IR+5-FU (30.32%) or IR+FOLFIRINOX therapy (43.04%) in inhibiting growth of the mouse Panc02 tumor. These encouraging results provide a solid foundation for clinical trials to improve the outcomes of the current standard chemoradiation therapy regimen for PDAC.


    Copyright © 2017. Published by Elsevier B.V.

    KEYWORDS: Chemoradiation, Chemoradiotherapy-resistance, Disulfiram, PDAC, Stem cells

    Publikations ID: 28864067
    Quelle: öffnen
     
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