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

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 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.

• Authors: 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
• Journal: Oncotarget (Oncotarget) Vol. 8 Issue 49 Pg. 85516-85525 (Oct 17 2017) ISSN: 1949-2553 [Electronic] United States
• PMID: 29156737 (Publication Type: Journal Article)