Tumor-targeting Salmonella typhimurium A1-R in combination with trastuzumab eradicates HER-2-positive cervical cancer cells in patient-derived mouse models

Yukihiko Hiroshima, Yong Zhang, Ming Zhao, Nan Zhang, Takashi Murakami, Ali Maawy, Sumiyuki Mii, Fuminari Uehara, Mako Yamamoto, Shinji Miwa, Shuya Yano, Masashi Momiyama, Ryutaro Mori, Ryusei Matsuyama, Takashi Chishima, Kuniya Tanaka, Yasushi Ichikawa, Michael Bouvet, Itaru Endo, Robert M. Hoffman

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40 Citations (Scopus)

Abstract

We have previously developed mouse models of HER-2-positive cervical cancer. Tumors in nude mice had histological structures similar to the original tumor and were stained by anti-HER-2 antibody in the same pattern as the patient's cancer. We have also previously developed tumor-targeting Salmonella typhimurium A1-R and have demonstrated its efficacy against patient-derived tumor mouse models, both alone and in combination. In the current study, we determined the efficacy of S. typhimurium A1-R in combination with trastuzumab on a patient-cancer nude-mouse model of HER-2 positive cervical cancer. Mice were randomized to 5 groups and treated as follows: (1) no treatment; (2) carboplatinum (30 mg/kg, ip, weekly, 5 weeks); (3) trastuzumab (20 mg/kg, ip, weekly, 5 weeks); (4) S. typhimurium A1-R (5 × 107 CFU/body, ip, weekly, 5 weeks); (5) S. typhimurium A1-R (5 × 107 CFU/body, ip, weekly, 5 weeks) + trastuzumab (20 mg/kg, ip, weekly, 5 weeks). All regimens had significant efficacy compared to the untreated mice. The relative tumor volume of S. typhimurium A1-R + trastuzumab-treated mice was smaller compared to trastuzumab alone (p = 0.007) and S. typhimurium A1-R alone (p = 0.039). No significant body weight loss was found compared to the no treatment group except for carboplatinum-treated mice (p = 0.021). Upon histological examination, viable tumor cells were not detected, and replaced by stromal cells in the tumors treated with S. typhimurium A1-R + trastuzumab. The results of the present study suggest that S. typhimurium A1-R and trastuzumab in combination are highly effective against HER-2-expressing cervical cancer.

Original languageEnglish
Article numbere0120358
JournalPloS one
Volume10
Issue number6
DOIs
Publication statusPublished - Jun 5 2015
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Hiroshima, Y., Zhang, Y., Zhao, M., Zhang, N., Murakami, T., Maawy, A., Mii, S., Uehara, F., Yamamoto, M., Miwa, S., Yano, S., Momiyama, M., Mori, R., Matsuyama, R., Chishima, T., Tanaka, K., Ichikawa, Y., Bouvet, M., Endo, I., & Hoffman, R. M. (2015). Tumor-targeting Salmonella typhimurium A1-R in combination with trastuzumab eradicates HER-2-positive cervical cancer cells in patient-derived mouse models. PloS one, 10(6), [e0120358]. https://doi.org/10.1371/journal.pone.0120358