title: Tumor-Targeting Salmonella typhimurium A1-R in Combination with Trastuzumab Eradicates HER-2-Positive Cervical Cancer Cells in Patient-Derived Mouse Models.
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.
authors.affiliation: AntiCancer, Inc., San Diego, California, United States of America; Department of Surgery, University of California San Diego, San Diego, California, United States of America; Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Hiroshima
authors.affiliation: AntiCancer, Inc., San Diego, California, United States of America.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: AntiCancer, Inc., San Diego, California, United States of America.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.affiliation: AntiCancer, Inc., San Diego, California, United States of America.
authors.forename: Nan
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Murakami
authors.affiliation: Department of Surgery, University of California San Diego, San Diego, California, United States of America.
authors.forename: Ali
authors.initials: A
authors.lastname: Maawy
authors.affiliation: AntiCancer, Inc., San Diego, California, United States of America; Department of Surgery, University of California San Diego, San Diego, California, United States of America.
authors.forename: Sumiyuki
authors.initials: S
authors.lastname: Mii
authors.affiliation: AntiCancer, Inc., San Diego, California, United States of America; Department of Surgery, University of California San Diego, San Diego, California, United States of America.
authors.forename: Fuminari
authors.initials: F
authors.lastname: Uehara
authors.affiliation: AntiCancer, Inc., San Diego, California, United States of America; Department of Surgery, University of California San Diego, San Diego, California, United States of America.
authors.forename: Mako
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: AntiCancer, Inc., San Diego, California, United States of America; Department of Surgery, University of California San Diego, San Diego, California, United States of America.
authors.forename: Shinji
authors.initials: S
authors.lastname: Miwa
authors.affiliation: AntiCancer, Inc., San Diego, California, United States of America; Department of Surgery, University of California San Diego, San Diego, California, United States of America.
authors.forename: Shuya
authors.initials: S
authors.lastname: Yano
authors.affiliation: Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Momiyama
authors.affiliation: Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Mori
authors.affiliation: Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Ryusei
authors.initials: R
authors.lastname: Matsuyama
authors.affiliation: Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Chishima
authors.affiliation: Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Kuniya
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Ichikawa
authors.affiliation: Department of Surgery, University of California San Diego, San Diego, California, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Bouvet
authors.affiliation: Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Itaru
authors.initials: I
authors.lastname: Endo
authors.affiliation: AntiCancer, Inc., San Diego, California, United States of America; Department of Surgery, University of California San Diego, San Diego, California, United States of America.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Hoffman
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D012486:Salmonella typhimurium / Q000502:physiology*; D014183:Transplantation, Heterologous; D000068878:Trastuzumab / Q000627:therapeutic use*; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human