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

doi:10.18632/oncotarget.9879

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.

Highlights

Sarcomas are a heterogeneous group of connective tissue malignancies of mesenchymal origin
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 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, cyclin-dependent kinase 4/6 (CDK4/6) inhibitor (palbociclib, PD0332991, per oral (p.o.), daily, for 14 days); G4, insulin-like growth factor-1 receptor (IGF-1R) inhibitor

Summary

Introduction

Sarcomas are a heterogeneous group of connective tissue malignancies of mesenchymal origin. They comprise approximately 1 percent of adult and 15 percent of pediatric malignancies. The most frequent site of primary sarcoma is the extremity, followed by the retroperitoneum and trunk. The most common site of metastasis is the lung. Sarcoma can metastasize to almost any location or organ. There are over 50 known histological sub-types of sarcoma. Ewing’s sarcoma is a rare malignancy in which EWS-FLI1 is considered to be the causal translocation for 90% of cases [1]. Treatment for Ewing’s sarcoma uses surgery, radiation, and chemotherapy but with poor outcome. Novel more effective treatment is necessary for this recalcitrant disease [2,3,4,5,6,7]

Objectives

Methods

Results

Conclusion