title: The irony of highly-effective bacterial therapy of a patient-derived orthotopic xenograft (PDOX) model of Ewing's sarcoma, which was blocked by Ewing himself 80 years ago.
abstract: William B. Coley developed bacterial therapy of cancer more than 100 years ago and had clinical success. James Ewing, a very famous cancer pathologist for whom the Ewing sarcoma is named, was Coley's boss at Memorial Hospital in New York and terminated Coley's bacterial therapy of cancer. A tumor from a patient with soft-tissue Ewing's sarcoma, who failed doxorubicin (DOX) therapy, was previously implanted in nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. In the present study, the Ewing's sarcoma PDOX was treated with tumor-targeting S. typhimurium A1-R expressing green fluorescent (GFP), alone and in combination with DOX. S. typhimurium A1-R-GFP was detected in the tumors after intratumor (i.t.) or intravenous (i.v.) injection. The combination of S. typhimurium A1-R and DOX significantly reduced tumor weight (37.8 ± 15.6 mg) compared to the untreated control (73.8 ± 10.1 mg, P < 0.01). S. typhimurium A1-R monotherapy-treated tumors tended to be smaller (50.9 ± 17.8 mg, P = 0.051). DOX monotherapy did not show efficacy (66.3 ± 26.4 mg, P = 0.82), as was the case with the patient. The PDOX model faithfully replicated the DOX resistance the Ewing's sarcoma had in the patient. S. typhimurium A1-R converted the Ewing's sarcoma from DOX resistant to sensitive. One can only wonder how bacterial therapy and immunotherapy of cancer would have developed over the past 80 years if Ewing did not stop Coley.
authors.affiliation: a AntiCancer, Inc. , San Diego , CA , USA.|b Department of Surgery , University of California , San Diego , CA , USA.|c Department of Gastroenterological Surgery , Graduate School of Medicine, Yokohama City University , Yokohama , Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Murakami
authors.affiliation: a AntiCancer, Inc. , San Diego , CA , USA.
authors.forename: Tasuku
authors.initials: T
authors.lastname: Kiyuna
authors.affiliation: a AntiCancer, Inc. , San Diego , CA , USA.
authors.forename: Kei
authors.initials: K
authors.lastname: Kawaguchi
authors.affiliation: a AntiCancer, Inc. , San Diego , CA , USA.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Igarashi
authors.affiliation: d Division of Hematology-Oncology , University of California , Los Angeles , CA , USA.
authors.forename: Arun S
authors.initials: AS
authors.lastname: Singh
authors.affiliation: c Department of Gastroenterological Surgery , Graduate School of Medicine, Yokohama City University , Yokohama , Japan.
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Hiroshima
authors.affiliation: a AntiCancer, Inc. , San Diego , CA , USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: a AntiCancer, Inc. , San Diego , CA , USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.affiliation: a AntiCancer, Inc. , San Diego , CA , USA.|b Department of Surgery , University of California , San Diego , CA , USA.|c Department of Gastroenterological Surgery , Graduate School of Medicine, Yokohama City University , Yokohama , Japan.
authors.forename: Kentaro
authors.identifier: http://orcid.org/0000-0002-4680-4317
authors.initials: K
authors.lastname: Miyake
authors.affiliation: e Department of Pathology , University of California , Los Angeles , CA , USA.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Nelson
authors.affiliation: e Department of Pathology , University of California , Los Angeles , CA , USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Dry
authors.affiliation: e Department of Pathology , University of California , Los Angeles , CA , USA.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Li
authors.affiliation: b Department of Surgery , University of California , San Diego , CA , USA.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: DeLong
authors.affiliation: b Department of Surgery , University of California , San Diego , CA , USA.
authors.forename: Thinzar M
authors.initials: TM
authors.lastname: Lwin
authors.affiliation: c Department of Gastroenterological Surgery , Graduate School of Medicine, Yokohama City University , Yokohama , Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Chishima
authors.affiliation: c Department of Gastroenterological Surgery , Graduate School of Medicine, Yokohama City University , Yokohama , Japan.
authors.forename: Kuniya
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: b Department of Surgery , University of California , San Diego , CA , USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Bouvet
authors.affiliation: c Department of Gastroenterological Surgery , Graduate School of Medicine, Yokohama City University , Yokohama , Japan.
authors.forename: Itaru
authors.identifier: http://orcid.org/0000-0001-5520-8114
authors.initials: I
authors.lastname: Endo
authors.affiliation: f Division of Surgical Oncology , University of California , Los Angeles , CA , USA.
authors.forename: Fritz C
authors.identifier: http://orcid.org/0000-0003-3336-9333
authors.initials: FC
authors.lastname: Eilber
authors.affiliation: a AntiCancer, Inc. , San Diego , CA , USA.|b Department of Surgery , University of California , San Diego , CA , USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Hoffman
mesh_terms: D000818:Animals; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D012486:Salmonella typhimurium / Q000502:physiology*; D012512:Sarcoma, Ewing / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D023041:Xenograft Model Antitumor Assays
chemical_list: D049452:Green Fluorescent Proteins; D004317:Doxorubicin
keywords: Ewing's sarcoma; PDOX; Salmonella typhimurium A1-R; bacterial therapy of cancer; patient-derived orthotopic xenograft