Open AccessCombination treatment with recombinant methioninase enables temozolomide to arrest a BRAF V600E melanoma in a patient-derived orthotopic xenograft (PDOX) mouse model
Author(s) -
Koji Kawaguchi,
Kentaro Igarashi,
Shukuan Li,
Qinghong Han,
Yuying Tan,
Tasuku Kiyuna,
Takashi Murakami,
Bartosz Chmielowski,
Scott D. Nelson,
Tara A. Russell,
Sarah Dry,
Yunfeng Li,
Michiaki Unno,
Fritz C. Eilber,
Robert M. Hoffman
Publication year - 2017
Publication title -
oncotarget
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.373
H-Index - 127
ISSN - 1949-2553
DOI - 10.18632/oncotarget.20231
Subject(s) - temozolomide , medicine , melanoma , cancer research , methionine , cancer , oncology , v600e , gerontology , chemotherapy , mutant , biology , genetics , gene , amino acid
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 previously-established 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.