Research Papers:

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, Kentaro Igarashi, Shukuan Li, Qinghong Han, Yuying Tan, Kentaro Miyake, Tasuku Kiyuna, Masuyo Miyake, Takashi Murakami, Bartosz Chmielowski, Scott D. Nelson, Tara A. Russell, Sarah M. Dry, Yunfeng Li5, Michiaki Unno, Fritz C. Eilber and Robert M. Hoffman _

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Oncotarget. 2018; 9:915-923. https://doi.org/10.18632/oncotarget.23185

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Kei Kawaguchi1,2,3, Kentaro Igarashi1,2, Shukuan Li1, Qinghong Han1, Yuying Tan1, Kentaro Miyake1,2, Tasuku Kiyuna1,2, Masuyo Miyake1,2, Takashi Murakami1,2, Bartosz Chmielowski4, Scott D. Nelson5, Tara A. Russell6, Sarah M. Dry5, Yunfeng Li5, Michiaki Unno3, Fritz C. Eilber6 and Robert M. Hoffman1,2

1AntiCancer, Inc., San Diego, CA, USA

2Department of Surgery, University of California, San Diego, CA, USA

3Department of Surgery, Graduate School of Medicine, Tohoku University, Sendai, Japan

4Division of Hematology-Oncology, University of California, Los Angeles, CA, USA

5Department of Pathology, University of California, Los Angeles, CA, USA

6Division of Surgical Oncology, University of California, Los Angeles, CA, USA

Correspondence to:

Robert M. Hoffman, email: [email protected]

Fritz C. Eilber, email: [email protected]

Keywords: melanoma; recombinant methioninase; methionine dependence; BRAF-V600E mutation; PDOX

Received: October 12, 2017     Accepted: November 19, 2017     Published: December 12, 2017


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.

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