Targeting altered cancer methionine metabolism with recombinant methioninase (rMETase) overcomes partial gemcitabine-resistance and regresses a patient-derived orthotopic xenograft (PDOX) nude mouse model of pancreatic cancer

Kei Kawaguchi, Kentaro Miyake, Qinghong Han, Shukuan Li, Yuying Tan, Kentaro Igarashi, Thinzar M. Lwin, Takashi Higuchi, Tasuku Kiyuna, Masuyo Miyake, Hiromichi Oshiro, Michael Bouvet, Michiaki Unno, Robert M. Hoffman

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Pancreatic cancer is a recalcitrant disease. Gemcitabine (GEM) is the most widely-used first-line therapy for pancreatic cancer, but most patients eventually fail. Transformative therapy is necessary to significantly improve the outcome of pancreatic cancer patients. Tumors have an elevated requirement for methionine and are susceptible to methionine restriction. The present study used a patient-derived orthotopic xenograft (PDOX) nude mouse model of pancreatic cancer to determine the efficacy of recombinant methioninase (rMETase) to effect methionine restriction and thereby overcome GEM-resistance. A pancreatic cancer obtained from a patient was grown orthotopically in the pancreatic tail of nude mice to establish the PDOX model. Five weeks after implantation, 40 pancreatic cancer PDOX mouse models were randomized into four groups of 10 mice each: untreated control (n = 10); GEM (100 mg/kg, i.p., once a week for 5 weeks, n = 10); rMETase (100 units, i.p., 14 consecutive days, n = 10); GEM+rMETase (GEM: 100 mg/kg, i.p., once a week for 5 weeks, rMETase: 100 units, i.p., 14 consecutive days, n = 10). Although GEM partially inhibited PDOX tumor growth, combination therapy (GEM+rMETase) was significantly more effective than mono therapy (GEM: p = 0.0025, rMETase: p = 0.0010). The present study is the first demonstrating the efficacy of rMETase combination therapy in a pancreatic cancer PDOX model to overcome first-line therapy resistance in this recalcitrant disease.

Original languageEnglish
Pages (from-to)868-873
Number of pages6
JournalCell Cycle
Volume17
Issue number7
DOIs
Publication statusPublished - 2018 May 1

Keywords

  • Gemcitabine
  • Methionine dependence
  • Nude mice
  • Orthotopic
  • Pancreatic cancer
  • Patientderived orthotopic xenograft (PDOX)
  • Precision therapy
  • Recombinant methioninase

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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