Tumor-targeting Salmonella typhimurium A1-R Sensitizes Melanoma with a BRAF-V600E Mutation to Vemurafenib in a Patient-derived Orthotopic Xenograft (PDOX) Nude Mouse Model.

Previously, a BRAF-V600E-mutant melanoma obtained from the right chest wall of a patient was grown orthotopically in the right chest wall of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. Tumor sizes were measured with calipers twice a week. On day 14 from initiation of treatment, trametinib (TRA), an MEK inhibitor, caused tumor regression. In contrast, another MEK inhibitor, cobimetinib (COB) could slow but not arrest growth or cause regression of the melanoma. First-line therapy temozolomide (TEM) could slow but not arrest tumor growth or cause regression. In addition, vemurafenib (VEM) was not effective even though VEM is supposed to target the BRAF-V600E mutation. We also previously demonstrated that tumor-targeting with S. typhimurium A1-R combined with TEM was significantly more effective than either S. typhimurium A1-R alone or TEM alone on the melanoma PDOX with a BRAF-V600E mutation. The present study used this PDOX model of melanoma to test its sensitivity to VEM combined with S. typhimurium A1-R compared to VEM alone and VEM combined with COB. VEM combined with S. typhimurium A1-R was significantly more effective than VEM alone or VEM combined with COB (p = 0.0216) which is currently first line therapy for advanced melanoma with BRAF-V600E mutation. This article is protected by copyright. All rights reserved.

Journal of cellular biochemistry. 2017 Jan 20 [Epub ahead of print]

Kei Kawaguchi, Kentaro Igarashi, Takashi Murakami, Ming Zhao, Yong Zhang, Bartosz Chmielowski, Tasuku Kiyuna, Scott D Nelson, Tara A Russell, Sarah M Dry, Yunfeng Li, Michiaki Unno, Fritz C Eilber, Robert M Hoffman

AntiCancer, Inc., San Diego, CA., Div. of Hematology-Oncology, University of California, Los Angeles, CA., Dept. of Pathology, University of California, Los Angeles, CA., Div. of Surgical Oncology, University of California, Los Angeles, CA., Dept. of Surgery, Graduate School of Medicine, Tohoku University, Sendai, Japan.