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Temsirolimus combined with cisplatin or bevacizumab is active in osteosarcoma models
Author(s) -
Fleuren Emmy D.G.,
VersleijenJonkers 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.
Publication year - 2014
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.28933
Subject(s) - temsirolimus , bevacizumab , medicine , osteosarcoma , cisplatin , in vivo , immunohistochemistry , pi3k/akt/mtor pathway , cancer research , positron emission tomography , oncology , pharmacology , pathology , apoptosis , nuclear medicine , discovery and development of mtor inhibitors , chemotherapy , biology , biochemistry , microbiology and biotechnology
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′‐ 18 F‐fluorothymidine ( 18 F‐FLT) positron emission tomography (PET) scans showed a remarkable decrease in 18 F‐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 18 F‐FLT‐PET demonstrated that responses as determined by caliper measurements underestimated the actual tumor response. Although 18 F‐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 18 F‐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.