Oncotarget

Research Papers:

Effective molecular targeting of CDK4/6 and IGF-1R in a rare FUS-ERG fusion CDKN2A-deletion doxorubicin-resistant Ewing's sarcoma patient-derived orthotopic xenograft (PDOX) nude-mouse model

Takashi Murakami _, Arun S. Singh, Tasuku Kiyuna, Sarah M. Dry, Yunfeng Li, Aaron W. James, Kentaro Igarashi, Kei Kawaguchi, Jonathan C. DeLong, Yong Zhang, Yukihiko Hiroshima, Tara Russell, Mark A. Eckardt, Jane Yanagawa, Noah Federman, Ryusei Matsuyama, Takashi Chishima, Kuniya Tanaka, Michael Bouvet, Itaru Endo, Fritz C. Eilber and Robert M. Hoffman

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Oncotarget. 2016; 7:47556-47564. https://doi.org/10.18632/oncotarget.9879

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Abstract

Takashi Murakami1,2,3, Arun S. Singh4, Tasuku Kiyuna1, Sarah M. Dry5, Yunfeng Li5, Aaron W. James5, Kentaro Igarashi1, Kei Kawaguchi1, Jonathan C. DeLong2, Yong Zhang1, Yukihiko Hiroshima3, Tara Russell6, Mark A. Eckardt6,7, Jane Yanagawa6, Noah Federman8, Ryusei Matsuyama3, Takashi Chishima3, Kuniya Tanaka3, Michael Bouvet2, Itaru Endo3, Fritz C. Eilber6,9, Robert M. Hoffman1,2,9,10

1AntiCancer, Inc., San Diego, CA, USA

2Department of Surgery, University of California, San Diego, CA, USA

3Department of Gastroenterological Surgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan

4Division of Hematology-Oncology, University of California, Los Angeles, CA, USA

5Department of Pathology, University of California, Los Angeles, CA, USA

6Division of Surgical Oncology, University of California, Los Angeles, CA, USA

7Department of Surgery, Yale University School of Medicine, New Haven, CT, USA

8Department of Pediatrics and Department of Orthopaedics, University of California, Los Angeles, CA, USA

9UCLA Sarcoma Program, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA

10PDOX Inc., San Diego, CA, USA

Correspondence to:

Robert M. Hoffman, email: [email protected]

Fritz C. Eilber, email: [email protected]

Keywords: palbociclib, linsitinib, patient-derived orthotopic xenograft, PDOX, Ewing’s sarcoma

Received: April 20, 2016    Accepted: May 22, 2016    Published: June 7, 2016

ABSTRACT

Ewing’s sarcoma is a rare and aggressive malignancy. In the present study, tumor from a patient with a Ewing’s sarcoma with cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) loss and FUS-ERG fusion was implanted in the right chest wall of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. The aim of the present study was to determine efficacy of cyclin-dependent kinase 4/6 (CDK4/6) and insulin-like growth factor-1 receptor (IGF-1R) inhibitors on the Ewing’s sarcoma PDOX. The PDOX models were randomized into the following groups when tumor volume reached 50 mm3: G1, untreated control; G2, doxorubicin (DOX) (intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, CDK4/6 inhibitor (palbociclib, PD0332991, per oral (p.o.), daily, for 14 days); G4, IGF-1R inhibitor (linsitinib, OSI-906, p.o., daily, for 14 days). Tumor growth was significantly suppressed both in G3 (palbociclib) and in G4 (linsitinib) compared to G1 (untreated control) at all measured time points. In contrast, DOX did not inhibit tumor growth at any time point, which is consistent with the failure of DOX to control tumor growth in the patient. The results of the present study demonstrate the power of the PDOX model to identify effective targeted molecular therapy of a recalcitrant DOX-resistant Ewing’s sarcoma with specific genetic alterations. The results of this study suggest the potential of PDOX models for individually-tailored, effective targeted therapy for recalcitrant cancer.


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