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Salmonella typhimurium A1-R targeting of a chemotherapy-resistant BRAF-V600E melanoma in a patient-derived orthotopic xenograft (PDOX) model is enhanced in combination with either vemurafenib or temozolomide

Kei KawaguchiAntiCancer, 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

Kentaro IgarashiAntiCancer, Inc., San Diego, CA, USA;Department of Surgery, University of California, San Diego, CA, USA

Takashi MurakamiAntiCancer, Inc., San Diego, CA, USA;Department of Surgery, University of California, San Diego, CA, USA

Tasuku KiyunaAntiCancer, Inc., San Diego, CA, USA;Department of Surgery, University of California, San Diego, CA, USA

Ming ZhaoAntiCancer, Inc., San Diego, CA, USA

Yong ZhangAntiCancer, Inc., San Diego, CA, USA

Scott D. NelsonDepartment of Pathology, University of California, Los Angeles, CA, USA

Tara A. RussellDivision of Surgical Oncology, University of California, Los Angeles, CA, USA

http://orcid.org/0000-0002-3912-3601

Sarah M. DryDepartment of Pathology, University of California, Los Angeles, CA, USA

Arun S. SinghDivision of Hematology-Oncology, University of California, Los Angeles, CA, USA

Bartosz ChmielowskiDivision of Hematology-Oncology, University of California, Los Angeles, CA, USA

http://orcid.org/0000-0002-2374-3320

Yunfeng LiDepartment of Pathology, University of California, Los Angeles, CA, USA

Michiaki UnnoDepartment of Surgery, Graduate School of Medicine, Tohoku University, Sendai, Japan

Fritz C. EilberDivision of Surgical Oncology, University of California, Los Angeles, CA, USACorrespondence[email protected]

http://orcid.org/0000-0003-3336-9333

Robert M. HoffmanAntiCancer, Inc., San Diego, CA, USA;Department of Surgery, University of California, San Diego, CA, USACorrespondence[email protected]

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ABSTRACT

A metastatic melanoma obtained from the right chest wall of a patient was previously established orthotopically in the right chest wall of nude mice as a patient-derived orthotopic xenograft (PDOX) model. We previously showed that the combination of tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R) and chemotherapy was highly effective against the melanoma PDOX. In the present study, we investigated the mechanism of the high efficacy of this combination. Two weeks after implantation, 40 PDOX mouse models were randomized into 4 groups of 10 mice each: untreated control (n = 10); treated with S. typhimurium A1-R (5 × 10⁷ CFU/100 μl, i.v., once a week for 2 weeks, n = 10); treated with temozolomide (TEM) (25 mg/kg, p.o. for 14 consecutive days) combined with S. typhimurium A1-R (5 × 10⁷ CFU/100 μl, i.v., once a week for 2 weeks, n = 10); treated with vemurafenib (VEM) (30 mg/kg, p.o., for 14 consecutive days) combined with S. typhimurium A1-R (5 × 10⁷ CFU/100 μl, i.v., once a week for 2 weeks) (n = 10). On day 14 from initiation, all treatments significantly inhibited tumor growth compared with untreated control (S. typhimurium A1-R: p < 0.01; TEM combined with S. typhimurium A1-R: p < 0.01; VEM combined with S. typhimurium A1-R: p < 0.01). Combination therapy with S. typhimurium A1-R was significantly more effective on tumor growth than S. typhimurium A1-R alone (with TEM: p < 0.01; with VEM: p < 0.01). Combination therapy significantly increased S. typhimurium A1-R tumor targeting alone (S. typhimurium A1-R + TEM: p < 0.01, S. typhimurium A1-R + VEM: p < 0.01), relative to S. typhimurium A1-R alone, respectively. In conclusion, chemotherapy drugs promoted targeting of S. typhimurium A1-R of melanoma, thereby enhancing efficacy against the melanoma PDOX.

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No potential conflicts of interest were disclosed.

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Salmonella typhimurium A1-R targeting of a chemotherapy-resistant BRAF-V600E melanoma in a patient-derived orthotopic xenograft (PDOX) model is enhanced in combination with either vemurafenib or temozolomide

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Salmonella typhimurium A1-R targeting of a chemotherapy-resistant BRAF-V600E melanoma in a patient-derived orthotopic xenograft (PDOX) model is enhanced in combination with either vemurafenib or temozolomide

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