Tumor-targeting Salmonella typhimurium A1-R suppressed an imatinib-resistant gastrointestinal stromal tumor with c-kit exon 11 and 17 mutations
Kentaro Miyake,
Kei Kawaguchi,
Masuyo Miyake,
Ming Zhao,
Tasuku Kiyuna,
Kentaro Igarashi,
Zhiying Zhang,
Takashi Murakami,
Yunfeng Li,
Scott D. Nelson,
Michael Bouvet,
Irmina Elliott,
Tara A. Russell,
Arun S. Singh,
Yukihiko Hiroshima,
Masashi Momiyama,
Ryusei Matsuyama,
Takashi Chishima,
Shree Ram Singh,
Itaru Endo,
Fritz C. Eilber,
Robert M. Hoffman
Affiliations
Kentaro Miyake
AntiCancer Inc., San Diego, CA, USA; Department of Surgery, University of California, San Diego, CA, USA; Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Kei Kawaguchi
AntiCancer Inc., San Diego, CA, USA; Department of Surgery, University of California, San Diego, CA, USA
Masuyo Miyake
AntiCancer Inc., San Diego, CA, USA; Department of Surgery, University of California, San Diego, CA, USA; Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Ming Zhao
AntiCancer Inc., San Diego, CA, USA
Tasuku Kiyuna
AntiCancer Inc., San Diego, CA, USA; Department of Surgery, University of California, San Diego, CA, USA
Kentaro Igarashi
AntiCancer Inc., San Diego, CA, USA; Department of Surgery, University of California, San Diego, CA, USA
Zhiying Zhang
AntiCancer Inc., San Diego, CA, USA; Department of Surgery, University of California, San Diego, CA, USA
Takashi Murakami
Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Yunfeng Li
Deptartment of Pathology, University of California, Los Angeles, CA, USA
Scott D. Nelson
Deptartment of Pathology, University of California, Los Angeles, CA, USA
Michael Bouvet
Department of Surgery, University of California, San Diego, CA, USA
Irmina Elliott
Division of Surgical Oncology, University of California, Los Angeles, CA, USA
Tara A. Russell
Division of Surgical Oncology, University of California, Los Angeles, CA, USA
Arun S. Singh
Division of Hematology-Oncology, University of California, Los Angeles, CA, USA
Yukihiko Hiroshima
Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Masashi Momiyama
Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Ryusei Matsuyama
Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Takashi Chishima
Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Shree Ram Singh
Basic Research Laboratory, National Cancer Institute, Frederick, MD, USA; Corresponding authors.
Itaru Endo
Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan; Corresponding authors.
Fritz C. Eilber
Division of Surgical Oncology, University of California, Los Angeles, CA, USA; Corresponding authors.
Robert M. Hoffman
AntiCancer Inc., San Diego, CA, USA; Department of Surgery, University of California, San Diego, CA, USA; Corresponding authors.
Gastrointestinal stromal tumor (GIST) is a refractory disease in need of novel efficacious therapy. The aim of our study was to evaluate the effectiveness of tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R) using on a patient derived orthotopic xenograft (PDOX) model of imatinib-resistant GIST. The GIST was obtained from a patient with regional recurrence, and implanted in the anterior gastric wall of nude mice. The GIST PDOX mice were randomized into 3 groups of 6 mice each when the tumor volume reached 60 mm3: G1, control group; G2, imatinib group (oral administration [p.o.], daily, for 3 weeks); G3, S. typhimurium A1-R group (intravenous [i.v.] injection, weekly, for 3 weeks). All mice from each group were sacrificed on day 22. Relative tumor volume was estimated by laparotomy on day 0 and day 22. Body weight of the mouse was evaluated 2 times per week. We found that S. typhimurium A1-R significantly reduced tumor growth in contrast to the untreated group (P = 0.001). In addition, we found that S. typhimurium A1-R was more effective compared to imatinib (P = 0.013). Furthermore, Imatinib was not significantly effective compared to the control group (P = 0.462). These results indicate that S. typhimurium A1-R may be new effective therapy for imatinib-resistant GIST and therefore a good candidate for clinical development of this disease.
