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.

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.

• Authors: 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, Robert M Hoffman
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 30 Pg. 47556-47564 (Jul 26 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27286459 (Publication Type: Journal Article)

Chemical References

• 3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol
• CDKN2A protein, human
• Cyclin-Dependent Kinase Inhibitor p16
• Cyclin-Dependent Kinase Inhibitor p18
• Imidazoles
• Oncogene Proteins, Fusion
• Piperazines
• Pyrazines
• Pyridines
• RNA-Binding Protein FUS
• TLS-ERG fusion protein, human
• Doxorubicin
• Receptor, IGF Type 1
• Cyclin-Dependent Kinase 4
• Cyclin-Dependent Kinase 6
• palbociclib

Topics

• Animals
• Bone Neoplasms (drug therapy, pathology)
• Cyclin-Dependent Kinase 4 (antagonists & inhibitors)
• Cyclin-Dependent Kinase 6 (antagonists & inhibitors)
• Cyclin-Dependent Kinase Inhibitor p16
• Cyclin-Dependent Kinase Inhibitor p18 (genetics)
• Doxorubicin (therapeutic use)
• Drug Resistance, Neoplasm
• Female
• Humans
• Imidazoles (therapeutic use)
• Mice
• Molecular Targeted Therapy
• Oncogene Proteins, Fusion (genetics)
• Piperazines (therapeutic use)
• Pyrazines (therapeutic use)
• Pyridines (therapeutic use)
• RNA-Binding Protein FUS (genetics)
• Receptor, IGF Type 1 (antagonists & inhibitors)
• Sarcoma, Ewing (drug therapy, pathology)
• Xenograft Model Antitumor Assays