Oncotarget

Research Papers:

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

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 and Robert M. Hoffman _

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Oncotarget. 2017; 8:85516-85525. https://doi.org/10.18632/oncotarget.20231

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Abstract

Kei Kawaguchi1,2,3, Kentaro Igarashi1,2, Shukuan Li1, Qinghong Han1, Yuying Tan1, Tasuku Kiyuna1,2, Kentaro 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: 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.


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