Intra-tumor L-methionine level highly correlates with tumor size in both pancreatic cancer and melanoma patient-derived orthotopic xenograft (PDOX) nude-mouse models
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Kei Kawaguchi1,2,3, Qinghong Han1, Shukuan Li1, Yuying Tan1, Kentaro Igarashi1,2, Kentaro Miyake1,2, Tasuku Kiyuna1,2, Masuyo Miyake1,2, Bartosz Chemielwski4, Scott D. Nelson5, Tara A. Russell6, Sarah M. Dry5, Yunfeng Li5, Arun S. Singh4, Mark A. Eckardt7, 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
7Department of Surgery, Yale School of Medicine, New Haven, CT, USA
Robert M. Hoffman, email: [email protected]
Fritz C. Eilber, email: [email protected]
Michiaki Unno, email: [email protected]
Keywords: recombinant methionine (rMETase); methionine dependence; tumor methionine; pancreatic cancer; melanoma
Received: December 23, 2017 Accepted: January 09, 2018 Published: January 17, 2018
An excessive requirement for methionine (MET) for growth, termed MET dependence, appears to be a general metabolic defect in cancer. We have previously shown that cancer-cell growth can be selectively arrested by MET restriction such as with recombinant methioninase (rMETase). In the present study, we utilized patient-derived orthotopic xenograft (PDOX) nude mouse models with pancreatic cancer or melanoma to determine the relationship between intra-tumor MET level and tumor size. After the tumors grew to 100 mm3, the PDOX nude mice were divided into two groups: untreated control and treated with rMETase (100 units, i.p., 14 consecutive days). On day 14 from initiation of treatment, intra-tumor MET levels were measured and found to highly correlate with tumor volume, both in the pancreatic cancer PDOX (p<0.0001, R2=0.89016) and melanoma PDOX (p<0.0001, R2=0.88114). Tumors with low concentration of MET were smaller. The present results demonstrates that patient tumors are highly dependent on MET for growth and that rMETase effectively lowers tumor MET.
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