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Efficacy of sunitinib and radiotherapy in genetically engineered mouse model of soft-tissue sarcoma.

ABSTRACT: Sunitinib (SU) is a multitargeted receptor tyrosine kinase inhibitor of the vascular endothelial growth factor and platelet-derived growth factor receptors. The present study examined SU and radiotherapy (RT) in a genetically engineered mouse model of soft tissue sarcoma (STS).Primary extremity STSs were generated in genetically engineered mice. The mice were randomized to treatment with SU, RT (10 Gy x 2), or both (SU+RT). Changes in the tumor vasculature before and after treatment were assessed in vivo using fluorescence-mediated tomography. The control and treated tumors were harvested and extensively analyzed.The mean fluorescence in the tumors was not decreased by RT but decreased 38-44% in tumors treated with SU or SU+RT. The control tumors grew to a mean of 1378 mm(3) after 12 days. SU alone or RT alone delayed tumor growth by 56% and 41%, respectively, but maximal growth inhibition (71%) was observed with the combination therapy. SU target effects were confirmed by loss of target receptor phosphorylation and alterations in SU-related gene expression. Cancer cell proliferation was decreased and apoptosis increased in the SU and RT groups, with a synergistic effect on apoptosis observed in the SU+RT group. RT had a minimal effect on the tumor microvessel density and endothelial cell-specific apoptosis, but SU alone or SU+RT decreased the microvessel density by >66% and induced significant endothelial cell apoptosis.SU inhibited STS growth by effects on both cancer cells and tumor vasculature. SU also augmented the efficacy of RT, suggesting that this combination strategy could improve local control of STS.

SUBMITTER: Yoon SS

PROVIDER: S-EPMC2733223 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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Efficacy of sunitinib and radiotherapy in genetically engineered mouse model of soft-tissue sarcoma.

Yoon Sam S SS Stangenberg Lars L Lee Yoon-Jin YJ Rothrock Courtney C Dreyfuss Jonathan M JM Baek Kwan-Hyuck KH Waterman Peter R PR Nielsen G Petur GP Weissleder Ralph R Mahmood Umar U Park Peter J PJ Jacks Tyler T Dodd Rebecca D RD Fisher Carolyn J CJ Ryeom Sandra S Kirsch David G DG

International journal of radiation oncology, biology, physics 20090701 4

<h4>Purpose</h4>Sunitinib (SU) is a multitargeted receptor tyrosine kinase inhibitor of the vascular endothelial growth factor and platelet-derived growth factor receptors. The present study examined SU and radiotherapy (RT) in a genetically engineered mouse model of soft tissue sarcoma (STS).<h4>Methods and materials</h4>Primary extremity STSs were generated in genetically engineered mice. The mice were randomized to treatment with SU, RT (10 Gy x 2), or both (SU+RT). Changes in the tumor vascu ...[more]

PMID: 19545786

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Project description:IntroductionAlthough the introduction of multimodal treatment of soft tissue sarcoma improved local tumour control, local failure still occurs in a good number of patients. Therefore, further improvement of current treatment strategies is necessary. The proposed study treatment will combine standard external beam radiation and the orally administered receptor tyrosine kinase inhibitor sunitinib.Methods and analysisPatients with soft tissue sarcoma will receive sunitinib and irradiation as neoadjuvant treatment. Radiotherapy will be administered as intensity modulated radiation therapy with a total dose of 50.4 Gy in 28 fractions (5 1/2 weeks). Patients will receive sunitinib daily for 2 weeks prior to and then concurrently with irradiation. Sunitinib will be given in two dose levels. The first dose level will be 25 mg sunitinib per os daily. The second dose level will be 37.5 mg. A dose modification schedule according to a 3+3 design will be applied. Restaging and tumour resection will be performed 6 weeks after completion of sunitinib and irradiation. Primary outcome measures will be the dose-limiting toxicity and maximal tolerated dose of sunitinib administered concurrently with irradiation. Toxicity of the study treatment will be documented according to Common Terminology Criteria of Adverse Events (CTCAE) 4.0. Secondary outcome measures will be the response to the study treatment and morbidity of the tumour resection. Imaging response will be determined according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria comparing MRI performed prior to and 6 weeks after completion of study treatment. Pathological response will be determined evaluating the fraction of non-viable tumour in the resection specimen. Resection morbidity will be evaluated according to CTCAE 4.0.Ethics and disseminationApproval was obtained from the ethics committee II of the University of Heidelberg, Germany (Reference number 2011-064F-MA). Furthermore, the study was approved by the German Federal Institute for Drugs and Medical Devices (Reference number 4037708).Trial registration eudract2007-002864-87 Clinicaltrials.gov: NCT01498835.

Dataset Information

Efficacy of sunitinib and radiotherapy in genetically engineered mouse model of soft-tissue sarcoma.

Publications

Efficacy of sunitinib and radiotherapy in genetically engineered mouse model of soft-tissue sarcoma.

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