Recombinant methioninase (rMETase) is an effective therapeutic for BRAF-V600E-negative as well as -positive melanoma in patient-derived orthotopic xenograft (PDOX) mouse models

// Kei Kawaguchi 1, 2, 3 , Kentaro Igarashi 1, 2 , Shukuan Li 1 , Qinghong Han 1 , Yuying Tan 1 , Kentaro Miyake 1, 2 , Tasuku Kiyuna 1, 2 , Masuyo 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: melanoma; recombinant methioninase; methionine dependence; BRAF-V600E mutation; PDOX Received: October 12, 2017 Accepted: November 19, 2017 Published: December 12, 2017 ABSTRACT Melanoma is a recalcitrant disease. Melanoma patients with the BRAF-V600E mutation have been treated with the drug vemurafenib (VEM) which targets this mutation. However, we previously showed that VEM is not very effective against a BRAF-V600E melanoma mutant in a patient-derived orthotopic xenograft (PDOX) model. In contrast, we demonstrated that recombinant methioninase (rMETase) which targets the general metabolic defect in cancer of methionine dependence, was effective against the BRAF-V600E mutant melanoma PDOX model. In the present study, we demonstrate that rMETase is effective against a BRAF-V600E-negative melanoma PDOX which we established. Forty BRAF-V600E-negative melanoma PDOX mouse models were randomized into four groups of 10 mice each: untreated control ( n = 10); temozolomide (TEM) (25 mg/kg, p.o., 14 consecutive days, n = 10); rMETase (100 units, i.p., 14 consecutive days, n = 10); TEM + rMETase (TEM: 25 mg/kg, p.o., rMETase: 100 units, i.p., 14 consecutive days, n = 10). All treatments inhibited tumor growth compared to untreated control (TEM: p = 0.0003, rMETase: p = 0.0006, TEM/rMETase: p = 0.0002) on day 14 after initiation. Combination therapy of TEM and rMETase was significantly more effective than either mono-therapy (TEM: p = 0.0113, rMETase: p = 0.0173). The present study shows that TEM combined with rMETase is effective for BRAF-V600E-negative melanoma PDOX similar to the BRAF-V600E-positive mutation melanoma. These results suggest rMETase in combination with first-line chemotherapy can be highly effective in both BRAF-V600E-negative as well as BRAF-V600E-positive melanoma and has clinical potential for this recalcitrant disease.