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

// Kei Kawaguchi 1, 2, 3 , Kentaro Igarashi 1, 2 , Shukuan Li 1 , Qinghong Han 1 , Yuying Tan 1 , Tasuku Kiyuna 1, 2 , Kentaro Miyake 1 , 2 , Takashi Murakami 1, 2 , Bartosz Chmielowski 4 , Scott D. Nelson 5 , Tara A. Russell 6 , Sarah M. Dry 5 , Yunfeng Li 5 , Michiaki Unno 3 , Fritz C. Eilber 6 and Robert M. Hoffman 1, 2 1 AntiCancer, Inc., San Diego, CA, USA 2 Department of Surgery, University of California, San Diego, CA, USA 3 Department of Surgery, Graduate School of Medicine, Tohoku University, Sendai, Japan 4 Division of Hematology-Oncology, University of California, Los Angeles, CA, USA 5 Department of Pathology, University of California, Los Angeles, CA, USA 6 Division of Surgical Oncology, University of California, Los Angeles, CA, USA Correspondence to: Robert M. Hoffman, email: all@anticancer.com Fritz C. Eilber, email: fceilber@mednet.ucla.edu Keywords: recombinant methioninase, methionine dependence, metabolic targeting, temozolomide, melanoma Received: June 06, 2017 Accepted: July 06, 2017 Published: August 12, 2017 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.