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  3. Oral recombinant methioninase increases TRAIL receptor-2 expression to regress pancreatic cancer in combination with agonist tigatuzumab in an orthotopic mouse model

Oral recombinant methioninase increases TRAIL receptor-2 expression to regress pancreatic cancer in combination with agonist tigatuzumab in an orthotopic mouse model

  • Cancer Lett. 2020 Nov 1;492:174-184. doi: 10.1016/j.canlet.2020.07.034.
Jun Yamamoto 1,  Kentaro Miyake 1,  Qinghong Han 2,  Yuying Tan 2,  Sachiko Inubushi 3,  Norihiko Sugisawa 3,  Takashi Higuchi 3,  Yoshihiko Tashiro 3,  Hiroto Nishino 3,  Yuki Homma 4,  Ryusei Matsuyama 4,  Sant P Chawla 5,  Michael Bouvet 6,  Shree Ram Singh 7,  Itaru Endo 8,  Robert M Hoffman 9
Affiliations

Affiliations

  • 1 AntiCancer Inc, San Diego, CA, USA; Department of Surgery, University of California, San Diego, CA, USA; Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
  • 2 AntiCancer Inc, San Diego, CA, USA.
  • 3 AntiCancer Inc, San Diego, CA, USA; Department of Surgery, University of California, San Diego, CA, USA.
  • 4 Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
  • 5 Sarcoma Oncology Center, Santa Monica, CA, USA.
  • 6 Department of Surgery, University of California, San Diego, CA, USA.
  • 7 Basic Research Laboratory, National Cancer Institute, Frederick, MD, USA. Electronic address: [email protected].
  • 8 Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan. Electronic address: [email protected].
  • 9 AntiCancer Inc, San Diego, CA, USA; Department of Surgery, University of California, San Diego, CA, USA. Electronic address: [email protected].
PMID: 32739322 DOI: 10.1016/j.canlet.2020.07.034
Abstract

Methionine addiction is a fundamental and general hallmark of Cancer. Gene expression analysis showed that methionine restriction (MR) of methionine-addicted Cancer cells increases TNF-related apoptosis-induced ligand receptor-2 (TRAIL-R2) expression. Here, we determined the effects of MR on TRAIL-R2 targeted therapy in pancreatic Cancer by the TRAIL-R2 agonist tigatuzumab. Human pancreatic Cancer cell lines were cultured in control or methionine-free medium. The effects of MR on TRAIL-R2 expression and sensitivity to tigatuzumab were evaluated in vitro. An orthotopic pancreatic Cancer mouse model was established to evaluate the efficacy of MR using oral recombinant methioninase (o-rMETase), and the efficacy of tigatuzumab and their combination. MR enabled tigatuzumab-induced Apoptosis, by increasing TRAIL-R2 expression in pancreatic Cancer cells in vitro. The protein expression level of the melanoma-associated antigen MAGED2, which reduces TRAIL-R2 expression, was decreased by MR. In the orthotopic pancreatic Cancer mouse model, o-rMETase increased TRAIL-R2 expression level in the tumors and enabled the antitumor efficacy of tigatuzumab. MR, effected by o-rMETase, enabled the efficacy of the TRAIL-R2 agonist tigatuzumab by increasing TRAIL-R2 expression in pancreatic Cancer. Our results suggest that o-rMETase has clinical potential for treating pancreatic Cancer.

Keywords

Methioninase; Methionine restriction; Pancreatic cancer; TRAIL-R2; Tigatuzumab.

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