TY - JOUR
T1 - 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) nudemouse model
AU - Murakami, Takashi
AU - Singh, Arun S.
AU - Kiyuna, Tasuku
AU - Dry, Sarah M.
AU - Li, Yunfeng
AU - James, Aaron W.
AU - Igarashi, Kentaro
AU - Kawaguchi, Kei
AU - DeLong, Jonathan C.
AU - Zhang, Yong
AU - Hiroshima, Yukihiko
AU - Russell, Tara
AU - Eckardt, Mark A.
AU - Yanagawa, Jane
AU - Federman, Noah
AU - Matsuyama, Ryusei
AU - Chishima, Takashi
AU - Tanaka, Kuniya
AU - Bouvet, Michael
AU - Endo, Itaru
AU - Eilber, Fritz C.
AU - Hoffman, Robert M.
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - Ewing's sarcoma
KW - Linsitinib
KW - PDOX
KW - Palbocicib
KW - Patient-derived orthotopic xenograft
UR - http://www.scopus.com/inward/record.url?scp=84982812991&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84982812991&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.9879
DO - 10.18632/oncotarget.9879
M3 - Article
C2 - 27286459
AN - SCOPUS:84982812991
VL - 7
SP - 47556
EP - 47564
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 30
ER -