Tumor-targeting Salmonella typhimurium A1-R combined with temozolomide regresses malignant melanoma with a BRAF-V600E mutation in a patient-derived orthotopic xenograft (PDOX) model.
Melanoma is a recalcitrant disease in need of transformative therapuetics. The present study used a patient-derived orthotopic xenograft (PDOX) nude-mouse model of melanoma with a BRAF-V600E mutation to determine the efficacy of temozolomide (TEM) combined with tumor-targeting Salmonella typhimurium A1-R. A melanoma obtained from the right chest wall of a patient was grown orthotopically in the right chest wall of nude mice to establish a PDOX model. Two weeks after implantation, 40 PDOX nude mice were divided into 4 groups: G1, control without treatment (n = 10); G2, TEM (25 mg/kg, administrated orally daily for 14 consecutive days, n = 10); G3, S. typhimurium A1-R (5 × 107 CFU/100 μl, i.v., once a week for 2 weeks, n = 10); G4, TEM combined with S. typhimurium A1-R (25 mg/kg, administrated orally daily for 14 consecutive days and 5 × 107 CFU/100 μl, i.v., once a week for 2 weeks, respectively, n = 10). Tumor sizes were measured with calipers twice a week. On day 14 from initiation of treatment, all treatments significantly inhibited tumor growth compared to untreated control (TEM: p < 0.0001; S. typhimurium A1-R: p < 0.0001; TEM combined with S. typhimurium A1-R: p < 0.0001). TEM combined with S. typhimurium A1-R was significantly more effective than either S. typhimurium A1-R (p = 0.0004) alone or TEM alone (p = 0.0017). TEM combined with S. typhimurium A1-R could regress the melanoma in the PDOX model and has important future clinical potential for melanoma patients.
AntiCancer, Inc., San Diego, CA, USA.|Department of Surgery, University of California, San Diego, CA, USA.|Department of Surgery, Graduate School of Medicine, Tohoku University, Sendai, Japan.
Kei
K
Kawaguchi
AntiCancer, Inc., San Diego, CA, USA.|Department of Surgery, University of California, San Diego, CA, USA.
Kentaro
K
Igarashi
AntiCancer, Inc., San Diego, CA, USA.|Department of Surgery, University of California, San Diego, CA, USA.
Takashi
T
Murakami
Division of Hematology-Oncology, University of California, Los Angeles, CA, USA.
Bartosz
B
Chmielowski
AntiCancer, Inc., San Diego, CA, USA.|Department of Surgery, University of California, San Diego, CA, USA.
Tasuku
T
Kiyuna
AntiCancer, Inc., San Diego, CA, USA.
Ming
M
Zhao
AntiCancer, Inc., San Diego, CA, USA.
Yong
Y
Zhang
Division of Hematology-Oncology, University of California, Los Angeles, CA, USA.
Arun
A
Singh
Department of Surgery, Graduate School of Medicine, Tohoku University, Sendai, Japan.
Michiaki
M
Unno
Department of Pathology, University of California, Los Angeles, CA, USA.
Scott D
SD
Nelson
Division of Surgical Oncology, University of California, Los Angeles, CA, USA.
Tara A
TA
Russell
Department of Pathology, University of California, Los Angeles, CA, USA.
Sarah M
SM
Dry
Department of Pathology, University of California, Los Angeles, CA, USA.
Yunfeng
Y
Li
Division of Surgical Oncology, University of California, Los Angeles, CA, USA.
Fritz C
FC
Eilber
AntiCancer, Inc., San Diego, CA, USA.|Department of Surgery, University of California, San Diego, CA, USA.
Robert M
RM
Hoffman
D000368:Aged; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012486:Salmonella typhimurium; D000077204:Temozolomide; D023041:Xenograft Model Antitumor Assays
D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D000077204:Temozolomide
PDOX; drug-response; melanoma; nude mice; orthotopic