The Combination of Olaratumab with Doxorubicin and Cisplatinum Regresses a Chemotherapy-Resistant Osteosarcoma in a Patient-Derived Orthotopic Xenograft Mouse Model

Takashi Higuchi; Norihiko Sugisawa; Kentaro Miyake; Hiromichi Oshiro; Norio Yamamoto; Katsuhiro Hayashi; Hiroaki Kimura; Shinji Miwa; Kentaro Igarashi; Michael Bouvet; Shree Ram Singh; Hiroyuki Tsuchiya; Robert M Hoffman

doi:10.1016/j.tranon.2019.06.002

The Combination of Olaratumab with Doxorubicin and Cisplatinum Regresses a Chemotherapy-Resistant Osteosarcoma in a Patient-Derived Orthotopic Xenograft Mouse Model

Transl Oncol. 2019 Sep;12(9):1257-1263. doi: 10.1016/j.tranon.2019.06.002. Epub 2019 Jul 9.

Affiliations

¹ AntiCancer, Inc., San Diego, CA, USA; Department of Surgery, University of California, San Diego, CA, USA; Department of Orthopedic Surgery, Kanazawa University, Kanazawa, Japan.
² AntiCancer, Inc., San Diego, CA, USA; Department of Surgery, University of California, San Diego, CA, USA.
³ Department of Orthopedic Surgery, Kanazawa University, Kanazawa, Japan.
⁴ Department of Surgery, University of California, San Diego, CA, USA.
⁵ Basic Research Laboratory, National Cancer Institute, Frederick, MD, USA. Electronic address: singhshr@mail.nih.gov.
⁶ Department of Orthopedic Surgery, Kanazawa University, Kanazawa, Japan. Electronic address: tsuchi@med.kanazawa-u.ac.jp.
⁷ AntiCancer, Inc., San Diego, CA, USA; Department of Surgery, University of California, San Diego, CA, USA. Electronic address: all@anticancer.com.

Abstract

Chemotherapy-resistant osteosarcoma is a recalcitrant disease. It is a frequent cause of death to the patients who are usually adolescent or young adults. The goal of the present study was to determine the efficacy of the combination of olaratumab (OLA), doxorubicin (DOX), and cisplatinum (CDDP) on osteosarcoma, which is resistant to first-line therapy, in a patient-derived orthotopic xenograft (PDOX) model. The osteosarcoma PDOX model was randomized into six treatment groups of six mice: control; CDDP alone; DOX and CDDP; OLA + DOX; OLA + CDDP; and OLA + DOX and CDDP. Tumor size and body weight were measured during 14 days of treatment. Tumor growth was regressed only by the treatment with a combination of OLA + DOX and CDDP. Tumors treated with this three-drug combination had the most tumor necrosis and the lowest Ki-67 index. The present study demonstrates the power of the PDOX model to identify novel effective treatment strategy for chemotherapy-resistant osteosarcoma.