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

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

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64 Citations (Scopus)

Abstract

Melanoma is a recalcitrant disease in need of transformative therapuetics. The present study used a patient-derived orthotopic xenograft (PDOX) nudemouse 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.

Original languageEnglish
Pages (from-to)85929-85936
Number of pages8
JournalOncotarget
Volume7
Issue number52
DOIs
Publication statusPublished - 2016 Jan 1

Keywords

  • Drug-response
  • Melanoma
  • Nude mice
  • Orthotopic
  • PDOX

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Kawaguchi, K., Igarashi, K., Murakami, T., Chmielowski, B., Kiyuna, T., Zhao, M., Zhang, Y., Singh, A., Unno, M., Nelson, S. D., Russell, T. A., Dry, S. M., Li, Y., Eilber, F. C., & Hoffman, R. M. (2016). 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. Oncotarget, 7(52), 85929-85936. https://doi.org/10.18632/oncotarget.13231