Combination treatment with recombinant methioninase enables temozolomide to arrest a BRAF V600E melanoma in a patientderived orthotopic xenograft (PDOX) mouse model

Kei Kawaguchi, Kentaro Igarashi, Shukuan Li, Qinghong Han, Yuying Tan, Tasuku Kiyuna, Kentaro Miyake, Takashi Murakami, Bartosz Chmielowski, Scott D. Nelson, Tara A. Russell, Sarah M. Dry, Yunfeng Li, Michiaki Unno, Fritz C. Eilber, Robert M. Hoffman

Research output: Contribution to journalArticlepeer-review

52 Citations (Scopus)

Abstract

An excessive requirement for methionine termed methionine dependence, appears to be a general metabolic defect in cancer. We have previously shown that cancer-cell growth can be selectively arrested by methionine deprivation such as with recombinant methioninase (rMETase). The present study used a previouslyestablished patient-derived orthotopic xenograft (PDOX) nude mouse model of BRAF V600E-mutant melanoma to determine the efficacy of rMETase in combination with a first-line melanoma drug, temozolomide (TEM). In the present study 40 melanoma PDOX mouse models were randomized into four groups of 10 mice each: untreated control (n=10); TEM (25 mg/kg, oral 14 consecutive days, n=10); rMETase (100 units, intraperitoneal 14 consecutive days, n=10); combination TEM + rMETase (TEM: 25 mg/kg, oral rMETase: 100 units, intraperitoneal 14 consecutive days, n=10). All treatments inhibited tumor growth compared to untreated control (TEM: p=0.0081, rMETase: p=0.0037, TEM-rMETase: p=0.0024) on day 14 after initiation. However, the combination therapy of TEM and rMETase was significantly more efficacious than either mono-therapy (TEM: p=0.0051, rMETase: p=0.0051). The present study is the first demonstrating the efficacy of rMETase combination therapy in a PDOX model, suggesting potential clinical development, especially in recalcitrant cancers such as melanoma, where rMETase may enhance first-line therapy.

Original languageEnglish
Pages (from-to)85516-85525
Number of pages10
JournalOncotarget
Volume8
Issue number49
DOIs
Publication statusPublished - 2017 Oct 17

Keywords

  • Melanoma
  • Metabolic targeting
  • Methionine dependence
  • Recombinant methioninase
  • Temozolomide

ASJC Scopus subject areas

  • Oncology

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