PURPOSE: Soft tissue sarcoma (STS) is a rare heterogeneous malignancy. Overall survival has been stagnant for decades, primarily because systemic therapies are ineffective versus metastases, the leading cause of STS lethality. Consequently, we examined whether tyrosine kinase receptors active in STS growth signaling might be blockable and whether multireceptor blockade might synergize with low-dose STS chemotherapy by therapeutically affecting STS cells and their associated microenvironment. EXPERIMENTAL DESIGN: Vandetanib (AstraZenca), a tyrosine kinase inhibitor of vascular endothelial growth factor receptor 2 and epidermal growth factor receptor, was evaluated alone and with chemotherapy in vitro and in vivo in three human STS nude mouse xenograft models of different STS locations (muscle, uterus, lung), stages (primary, metastatic), and subtypes (leiomyosarcoma, fibrosarcoma, uterine sarcoma: luciferase-expressing MES-SA human uterine sarcoma cells surgically implanted into uterine muscularis with bioluminescence tumor growth assessment; developed by us). RESULTS: In vitro, human STS cells were sensitive to vandetanib. Vandetanib alone and with chemotherapy statistically significantly inhibited leiomyosarcoma local growth and fibrosarcoma lung metastasis. Direct injection of MES-SA into nude mice uterine muscularis resulted in high tumor take (88%), whereas s.c. injection resulted in no growth, suggesting microenvironmental tumor growth modulation. Vandetanib alone and with chemotherapy statistically significantly inhibited uterine sarcoma growth. In all models, vandetanib induced increased apoptosis, decreased tumor cell proliferation, and decreased angiogenesis. CONCLUSIONS: Vandetanib has antitumor effects against human STS subtypes in vitro and in vivo, where it also affects the tumor-associated microenvironment. Given the urgent need for better systemic approaches to STS, clinical trials evaluating vandetanib, perhaps with low-dose chemotherapy, seem warranted.
PURPOSE: Soft tissue sarcoma (STS) is a rare heterogeneous malignancy. Overall survival has been stagnant for decades, primarily because systemic therapies are ineffective versus metastases, the leading cause of STS lethality. Consequently, we examined whether tyrosine kinase receptors active in STS growth signaling might be blockable and whether multireceptor blockade might synergize with low-dose STS chemotherapy by therapeutically affecting STS cells and their associated microenvironment. EXPERIMENTAL DESIGN: Vandetanib (AstraZenca), a tyrosine kinase inhibitor of vascular endothelial growth factor receptor 2 and epidermal growth factor receptor, was evaluated alone and with chemotherapy in vitro and in vivo in three human STS nude mouse xenograft models of different STS locations (muscle, uterus, lung), stages (primary, metastatic), and subtypes (leiomyosarcoma, fibrosarcoma, uterine sarcoma: luciferase-expressing MES-SA human uterine sarcoma cells surgically implanted into uterine muscularis with bioluminescence tumor growth assessment; developed by us). RESULTS: In vitro, human STS cells were sensitive to vandetanib. Vandetanib alone and with chemotherapy statistically significantly inhibited leiomyosarcoma local growth and fibrosarcoma lung metastasis. Direct injection of MES-SA into nude mice uterine muscularis resulted in high tumor take (88%), whereas s.c. injection resulted in no growth, suggesting microenvironmental tumor growth modulation. Vandetanib alone and with chemotherapy statistically significantly inhibited uterine sarcoma growth. In all models, vandetanib induced increased apoptosis, decreased tumor cell proliferation, and decreased angiogenesis. CONCLUSIONS: Vandetanib has antitumor effects against human STS subtypes in vitro and in vivo, where it also affects the tumor-associated microenvironment. Given the urgent need for better systemic approaches to STS, clinical trials evaluating vandetanib, perhaps with low-dose chemotherapy, seem warranted.
Authors: Xianbiao Xie; Markus P H Ghadimi; Eric D Young; Roman Belousov; Quan-Sheng Zhu; Juehui Liu; Gonzalo Lopez; Chiara Colombo; Tingsheng Peng; David Reynoso; Jason L Hornick; Alexander J Lazar; Dina Lev Journal: Clin Cancer Res Date: 2011-08-05 Impact factor: 12.531
Authors: Suizhao Wang; Wenhong Ren; Jeffery Liu; Guy Lahat; Keila Torres; Gonzalo Lopez; Alexander J Lazar; Andrea Hayes-Jordan; Kebin Liu; Jim Bankson; John D Hazle; Dina Lev Journal: Clin Cancer Res Date: 2010-04-20 Impact factor: 12.531
Authors: Christine M Kivlin; Kelsey L Watson; Ghadah A Al Sannaa; Roman Belousov; Davis R Ingram; Kai-Lieh Huang; Caitlin D May; Svetlana Bolshakov; Sharon M Landers; Azad Abul Kalam; John M Slopis; Ian E McCutcheon; Raphael E Pollock; Dina Lev; Alexander J Lazar; Keila E Torres Journal: Cancer Biol Ther Date: 2015-12-09 Impact factor: 4.742
Authors: Jia-Jean Yiin; Bo Hu; Paul A Schornack; Raghvendra S Sengar; Kun-Wei Liu; Haizhong Feng; Frank S Lieberman; Shih-Hwa Chiou; Jann N Sarkaria; Erik C Wiener; Hsin-I Ma; Shi-Yuan Cheng Journal: Mol Cancer Ther Date: 2010-04-06 Impact factor: 6.261