Exquisite Tumor Targeting by Salmonella A1-R in Combination with Caffeine and Valproic Acid Regresses an Adult Pleomorphic Rhabdomyosarcoma Patient-Derived Orthotopic Xenograft Mouse Model

Kentaro Igarashi; Kei Kawaguchi; Ming Zhao; Tasuku Kiyuna; Kentaro Miyake; Masuyo Miyake; Scott D. Nelson; Sarah M. Dry; Yunfeng Li; Norio Yamamoto; Katsuhiro Hayashi; Hiroaki Kimura; Shinji Miwa; Takashi Higuchi; Shree Ram Singh; Hiroyuki Tsuchiya; Robert M. Hoffman

Translational Oncology (Feb 2020)

Exquisite Tumor Targeting by Salmonella A1-R in Combination with Caffeine and Valproic Acid Regresses an Adult Pleomorphic Rhabdomyosarcoma Patient-Derived Orthotopic Xenograft Mouse Model

Kentaro Igarashi,
Kei Kawaguchi,
Ming Zhao,
Tasuku Kiyuna,
Kentaro Miyake,
Masuyo Miyake,
Scott D. Nelson,
Sarah M. Dry,
Yunfeng Li,
Norio Yamamoto,
Katsuhiro Hayashi,
Hiroaki Kimura,
Shinji Miwa,
Takashi Higuchi,
Shree Ram Singh,
Hiroyuki Tsuchiya,
Robert M. Hoffman

Affiliations

Kentaro Igarashi: AntiCancer, Inc., San Diego, CA, USA; Department of Surgery, University of California, San Diego, CA, USA; Department of Orthopaedic Surgery, Kanazawa University, Kanazawa, Japan
Kei Kawaguchi: AntiCancer, Inc., San Diego, CA, USA; Department of Surgery, University of California, San Diego, CA, USA
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 Miyake: 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
Scott D. Nelson: Department of Pathology, University of California, Los Angeles, CA, USA
Sarah M. Dry: Department of Pathology, University of California, Los Angeles, CA, USA
Yunfeng Li: Department of Pathology, University of California, Los Angeles, CA, USA
Norio Yamamoto: Department of Orthopaedic Surgery, Kanazawa University, Kanazawa, Japan
Katsuhiro Hayashi: Department of Orthopaedic Surgery, Kanazawa University, Kanazawa, Japan
Hiroaki Kimura: Department of Orthopaedic Surgery, Kanazawa University, Kanazawa, Japan
Shinji Miwa: Department of Orthopaedic Surgery, Kanazawa University, Kanazawa, Japan
Takashi Higuchi: AntiCancer, Inc., San Diego, CA, USA; Department of Surgery, University of California, San Diego, CA, USA; Department of Orthopaedic Surgery, Kanazawa University, Kanazawa, Japan
Shree Ram Singh: Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA; Address all correspondence to: Shree Ram Singh, PhD, Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.
Hiroyuki Tsuchiya: Department of Orthopaedic Surgery, Kanazawa University, Kanazawa, Japan; Hiroyuki Tsuchiya, MD, PhD, Department of Orthopaedic Surgery, Graduate School of Medicine, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan.
Robert M. Hoffman: AntiCancer, Inc., San Diego, CA, USA; Department of Surgery, University of California, San Diego, CA, USA; Robert M. Hoffman, PhD, AntiCancer, Inc., 7917 Ostrow Street, San Diego, CA 92111, USA.

Journal volume & issue: Vol. 13, no. 2
pp. 393 – 400

Abstract

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Adult pleomorphic rhabdomyosarcoma (RMS) is a rare and malignant mesenchymal tumor. Recently, we developed a patient-derived orthotopic xenograft (PDOX) model of adult pleomorphic RMS. In the present study, we evaluated the efficacy of tumor-targeting Salmonella typhimurium (S. typhimurium) A1-R combined with caffeine (CAF) and valproic acid (VPA) on the adult RMS PDOX. An adult pleomorphic RMS cell line was established from the PDOX model. Cell survival after exposure to CAF and VPA was assessed, and the IC50 value was calculated for each drug. The RMS PDOX models were randomized into five groups: untreated control; tumor treated with cyclophosphamide (CPA); tumor treated with CAF + VPA; tumor treated with S. typhimurium A1-R; and tumor treated with S. typhimurium A1-R + CAF + VPA. Tumor size and body weight was measured twice a week. VPA caused a concentration-dependent cytocidal effect. A synergistic effect of combination treatment with CAF was observed against the RMS cell line. For the in vivo study, all treatments significantly inhibited tumor growth compared with the untreated control. S. typhimurium A1-R combined with VPA and CAF was significantly more effective than CPA, VPA combined with CAF, or S. typhimurium A1-R alone and significantly regressed the tumor volume compared with day 0. These results suggest that S. typhimurium A1-R together with VPA and CAF could regresses an adult pleomorphic RMS in a PDOX model and therefore has important future clinical potential.

Published in Translational Oncology

ISSN: 1944-7124 (Print); 1936-5233 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: https://www.journals.elsevier.com/translational-oncology/

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