High Efficacy of Pazopanib on an Undifferentiated Spindle-Cell Sarcoma Resistant to First-Line Therapy Is Identified With a Patient-Derived Orthotopic Xenograft (PDOX) Nude Mouse Model

Abstract

Undifferentiated spindle‐cell sarcoma (USCS) is a recalcitrant ­cancer. Our laboratory pioneered the patient‐derived orthotopic xenograft (PDOX) nude mouse model with the technique of surgical orthotopic implantation (SOI). In the present study, we evaluated the efficacy of standard first‐line chemistry of doxorubicin (DOX), gemcitabine (GEM) combined with docetaxel (DOC), compared to pazopanib (PAZ), a multi‐targeting tyrosine‐kinase inhibitor, in an USCS PDOX model. A high‐grade USCS from a striated muscle of the patients was grown orthotopically in the right biceps femoris muscle of nude mice to establish the PDOX model. The PDOX models were randomized into the following groups when tumor volume reached 100 mm3: G1, control without treatment; G2, DOX (3 mg/kg, intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, GEM (100 mg/kg, i.p., weekly, for 2 weeks) combined with DOC (20 mg/kg, i.p., once); G4, PAZ (100 mg/kg, p.o., daily, for 14 days). All treatments except DOX significantly inhibited tumor growth compared to untreated control on day 14 after treatment initiation. Tumor sizes were as fallows: control (G1): 332.0 ± 58.7 mm3; DOX (G2): 316.9 ± 55.9 mm3, P = 0.605; GEM + DOC (G3): 228.9 ± 39.8 mm3, P = 0.001; PAZ (G4): 173.8 ± 23.3 mm3, P < 0.0001. PAZ showed significantly more efficacy compared to other therapies evaluated: DOX (P < 0.0001), GEM + DOC (P = 0.006). There were no animal deaths in any group and body weight of treated mice was not significantly different in each group. The present results demonstrate that the PDOX model of USCS can identify a promising novel agent with significantly greater efficacy than first‐line therapy for this recalcitrant disease. J. Cell. Biochem. 118: 2739–2743, 2017. © 2017 Wiley Periodicals, Inc.

Visualizing the Tumor Microenvironment by Color-coded Imaging in Orthotopic Mouse Models of Cancer

“…Recently, PDOX models of sarcoma (47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64), cervical cancer (65-67) as well as melanoma (68)(69)(70)(71)(72)(73)(74) have also been developed.…”

Temozolomide regresses a doxorubicin‐resistant undifferentiated spindle‐cell sarcoma patient‐derived orthotopic xenograft (PDOX): precision‐oncology nude‐mouse model matching the patient with effective therapy

“…PDOX models of sarcoma that we have developed include undifferentiated pleomorphic sarcoma (UPS), follicular dendritic cell sarcoma (FDCS), rhabdomyosarcoma (RMS), Ewing's sarcoma, and osteosaroma . The present report describes a DOX‐resistant PDOX model of undifferentiated spindle‐cell sarcoma (USCS) which is highly sensitive to TEM …”

“…The patient did not receive any chemotherapy or radiotherapy prior to surgery. Written informed consent was previously obtained from the patient as part of a UCLA Institutional Review Board approved protocol (IRB #10‐001857) …”

“…After nude mice were anesthetized with the ketamine‐mixture (see above), a 5 mm skin incision was made on the right high thigh, the biceps femoris was split, and a single tumor fragment was implanted orthotopically into the space to establish the PDOX model. The wound was closed with a 6‐0 nylon suture (Ethilon, Ethicon, Inc., NJ) …”

Anti‐tumor effects of a nonsteroidal anti‐inflammatory drug zaltoprofen on chondrosarcoma via activating peroxisome proliferator‐activated receptor gamma and suppressing matrix metalloproteinase‐2 expression

“…Therefore, these findings suggest that zaltoprofen could be a novel promising remedy against chondrosarcomas via PPARγ activation and MMP2 inhibition. Future studies using orthotopic xenograft mouse models will be required to show the in vivo effect of zaltoprofen on chondrosarcomas, based on previous reports of osteosarcoma [33,34], rhabdomyosarcoma [35], and undifferentiated pleomorphic sarcoma [36][37][38] with various anti-cancer drugs. In addition, large prospective cohort studies will be required to draw a final conclusion about the efficacy of zaltoprofen and to evaluate the effect of clinical applications in patients with chondrosarcoma.…”