Abstract 2761: Temsirolimus is effective as a single agent and in combination with cisplatin or bevacizumab in preclinical osteosarcoma models.
Authors: Fleuren Emmy DG , Versleijen-Jonkers Yvonne MH , Roeffen Melissa HS , Franssen Gerben M. , Houghton Peter J. , Oyen Wim JG , Boerman Otto C. , van der Graaf Winette TA 
Published: August 2014

Introduction: Osteosarcoma is the most commonly diagnosed primary malignant bone tumor occurring in children and adolescents. Despite multimodal treatment the final outcome has not improved impressively during the last decades and side-effects of treatment could be severe. There is an urgent need for novel therapeutic approaches. Blocking mTOR signaling appeared a promising treatment option. However, in patients at best partial responses were seen during mTOR-targeted monotherapies. We hypothesized that the addition of other drugs may improve the therapeutic efficacy of mTOR-inhibitors. In this study, we examined the effects of the mTOR-inhibitor temsirolimus on the growth of human osteosarcoma xenografts in vivo, with and without chemotherapy (cisplatin) or a VEGF-inhibitor (bevacizumab).

Methods: BALB/c nude mice were s.c. implanted with human osteosarcoma xenografts (OS-33 or OS-1; from PPTP) and treated with temsirolimus (1 mg/kg, every 3 days), cisplatin (3.5 mg/kg, every 21 days), bevacizumab (5 mg/kg, twice weekly), temsirolimus + cisplatin (TC) or temsirolimus + bevacizumab (TB) for 4 weeks (n=8-10 mice per group). Tumor growth was monitored by caliper measurements twice weekly. Relative tumor volumes (RTV) were used to compare tumor growth in the groups. Reductions in tumor volumes were expressed as percentage reduction compared to tumors in control mice at the end of the experiment.

Results: Temsirolimus monotherapy significantly inhibited growth of OS-1 (24%, p=0.025) and OS-33 (60%, p=0.01) tumors as compared to controls. TC treatment resulted in significantly enhanced tumor growth inhibition compared to each monotherapy in mice with OS-1 tumors (cisplatin: 16%, p=0.13; TC: 49%, p&lt;0.01) and with OS-33 tumors (cisplatin: 61%, p=0.01; TC: 85%, p&lt;0.01). This effect was synergistic in OS-1 tumors, because these tumors were resistant to cisplatin monotherapy. Also in TB treated mice, significantly better anti-tumor responses were observed compared to the monotherapies in both OS-1 (bevacizumab: 35%, p&lt;0.01; TB: 57%, p&lt;0.01) and OS-33 models (bevacizumab: 70%, p=0.01; TB: 91%, p&lt;0.01). All therapies were tolerated well.

Conclusion: Temsirolimus is effective as a single agent in OS-1 and OS-33 osteosarcoma models, but the combination with cisplatin or bevacizumab induced a superior anti-tumor response compared to all monotherapies. These data indicate that temsirolimus, combined with cisplatin or bevacizumab, should be further explored in the treatment of osteosarcoma patients.We are currently analyzing the effect of these treatments on tumor proliferation and vascularization by IHC, and are exploring the possible use of 18F-FDG- and 18F-FLT-PET scans for the in vivo monitoring of therapy response. This research was supported by Pfizer.

Citation Format: Emmy DG Fleuren, Yvonne MH Versleijen-Jonkers, Melissa HS Roeffen, Gerben M. Franssen, Peter J. Houghton, Wim JG Oyen, Otto C. Boerman, Winette TA van der Graaf. Temsirolimus is effective as a single agent and in combination with cisplatin or bevacizumab in preclinical osteosarcoma models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2761. doi:10.1158/1538-7445.AM2013-2761