Temsirolimus combined with cisplatin or bevacizumab is active in osteosarcoma models

• Published in: International journal of cancer Vol. 135; no. 12; pp. 2770 - 2782
• Main Authors: Fleuren, Emmy D.G., Versleijen‐Jonkers, Yvonne M.H., Roeffen, Melissa H.S., Franssen, Gerben M., Flucke, Uta E., Houghton, Peter J., Oyen, Wim J.G., Boerman, Otto C., Graaf, Winette T.A.
• Format: Journal Article
• Language: English
• Published: Hoboken, NJ Wiley-Blackwell 15.12.2014; Wiley Subscription Services, Inc
• Subjects: 18F‐FLT‐PET; Angiogenesis Inhibitors - administration & dosage; Animals; Antibodies, Monoclonal, Humanized - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Bevacizumab; Biological and medical sciences; Bone Neoplasms - drug therapy; Cancer; Cell Line, Tumor; Chemotherapy; cisplatin; Cisplatin - administration & dosage; Dideoxynucleosides; Diseases of the osteoarticular system; Female; Fluorodeoxyglucose F18; Humans; Medical imaging; Medical research; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); osteosarcoma; Osteosarcoma - drug therapy; Pharmacology; Positron-Emission Tomography; Protein Kinase Inhibitors - administration & dosage; Sirolimus - administration & dosage; Sirolimus - analogs & derivatives; temsirolimus; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases - metabolism; Tumors; Tumors of striated muscle and skeleton; Xenograft Model Antitumor Assays; Radionuclide study; Antineoplastic agent; Sarcoma; Diseases of the osteoarticular system; Temsirolimus; Monoclonal antibody; Malignant tumor; Cisplatin; Bevacizumab; Osteoarticular system; Immunomodulator; Alkylating agent; Cancerology; Vascular endothelium growth factor; Osteosarcoma; Models; Immunosuppressive agent; Bone; Antiangiogenic agent; F-FLT-PET; Positron emission tomography; Cancer; Platinum II Complexes; Emission tomography; bevacizumab; temsirolimus; cisplatin; 18F-FLT-PET; osteosarcoma
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.28933

Mammalian target of rapamycin (mTOR) is a new promising oncological target. However, most clinical studies reported only modest antitumor activity during mTOR‐targeted monotherapies, including studies in osteosarcomas, emphasizing a need for improvement. We hypothesized that the combination with rationally selected other therapeutic agents may improve response. In this study, we examined the efficacy of the mTOR inhibitor temsirolimus combined with cisplatin or bevacizumab on the growth of human osteosarcoma xenografts (OS‐33 and OS‐1) in vivo, incorporating functional imaging techniques and microscopic analyses to unravel mechanisms of response. In both OS‐33 and OS‐1 models, the activity of temsirolimus was significantly enhanced by the addition of cisplatin (TC) or bevacizumab (TB). Extensive immunohistochemical analysis demonstrated apparent effects on tumor architecture, vasculature, apoptosis and the mTOR‐pathway with combined treatments. 3′‐Deoxy‐3′‐18F‐fluorothymidine (18F‐FLT) positron emission tomography (PET) scans showed a remarkable decrease in 18F‐FLT signal in TC‐ and TB‐treated OS‐1 tumors, which was already noticeable after 1 week of treatment. No baseline uptake was observed in the OS‐33 model. Both immunohistochemistry and 18F‐FLT‐PET demonstrated that responses as determined by caliper measurements underestimated the actual tumor response. Although 18F‐FLT‐PET could be used for accurate and early response monitoring for temsirolimus‐based therapies in the OS‐1 model, we could not evaluate OS‐33 tumors with this molecular imaging technique. Further research on the value of the use of 18F‐FLT‐PET in this setting in osteosarcomas is warranted. Overall, these findings urge the further exploration of TC and TB treatment for osteosarcoma (and other cancer) patients. What's new? Blockade of mammalian target of rapamycin (mTOR) represents a promising approach in the treatment of osteosarcoma, although mTOR monotherapy has met with mixed results in patients. This study suggests that combination therapy may be the key to success. Using in vivo osteosarcoma models, the authors show that the activity of the mTOR‐inhibitor temsirolimus is significantly enhanced by the addition of cisplatin or bevacizumab. In addition, immunohistochemical and 18F‐FLT‐PET analyses of tumor response indicate that tumor volumes underestimate treatment efficacy, highlighting the importance of incorporating functional imaging techniques for accurate tumor monitoring in osteosarcoma.