Salmonella typhimuriumA1-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

ABSTRACTA 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 typhimuriumA1-R (S. typhimuriumA1-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. typhimuriumA1-R (5 × 107CFU/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. typhimuriumA1-R (5 × 107CFU/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. typhimuriumA1-R (5 × 107CFU/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. typhimuriumA1-R: p< 0.01; TEM combined with S. typhimuriumA1-R: p< 0.01; VEM combined with S. typhimuriumA1-R: p< 0.01). Combination therapy with S. typhimuriumA1-R was significantly more effective on tumor growth than S. typhimuriumA1-R alone (with TEM: p< 0.01; with VEM: p< 0.01). Combination therapy significantly increased S. typhimuriumA1-R tumor targeting alone (S. typhimuriumA1-R + TEM: p< 0.01, S. typhimuriumA1-R + VEM: p< 0.01), relative to S. typhimuriumA1-R alone, respectively. In conclusion, chemotherapy drugs promoted targeting of S. typhimuriumA1-R of melanoma, thereby enhancing efficacy against the melanoma PDOX.