Tumor-targeting Salmonella typhimurium A1-R suppressed an imatinib-resistant gastrointestinal stromal tumor with c-kit exon 11 and 17 mutations

Author:

Miyake, Kentaro

Kawaguchi, Kei

Miyake, Masuyo

Zhao, Ming

Kiyuna, Tasuku

Igarashi, Kentaro

Zhang, Zhiying

Murakami, Takashi

Li, Yunfeng

Nelson, Scott D

Bouvet, Michael

Elliott, Irmina

Russell, Tara A

Singh, Arun S

Hiroshima, Yukihiko

Momiyama, Masashi

Matsuyama, Ryusei

Chishima, Takashi

Singh, Shree Ram

Endo, Itaru

Eilber, Fritz C

Hoffman, Robert M
Author Address

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., Deptartment of Pathology, University of California, Los Angeles, CA, USA., Division of Surgical Oncology, University of California, Los Angeles, CA, USA., Division of Hematology-Oncology, University of California, Los Angeles, CA, USA., Basic Research Laboratory, National Cancer Institute, Frederick, MD, USA.,

Abstract:

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.

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