title: Combined vascular endothelial growth factor receptor/epidermal growth factor receptor blockade with chemotherapy for treatment of local, uterine, and metastatic soft tissue sarcoma.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.affiliation: Department of Surgical Oncology, University of Texas, M D Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Wenhong
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authors.lastname: Ren
authors.forename: Borys
authors.initials: B
authors.lastname: Korchin
authors.forename: Guy
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authors.lastname: Lahat
authors.forename: Caimiao
authors.initials: C
authors.lastname: Wei
authors.forename: Svetlana
authors.initials: S
authors.lastname: Bolshakov
authors.forename: Theresa
authors.initials: T
authors.lastname: Nguyen
authors.forename: William
authors.initials: W
authors.lastname: Merritt
authors.forename: Adam
authors.initials: A
authors.lastname: Dicker
authors.forename: Alexander
authors.initials: A
authors.lastname: Lazar
authors.forename: Anil
authors.initials: A
authors.lastname: Sood
authors.forename: Raphael E
authors.initials: RE
authors.lastname: Pollock
authors.forename: Dina
authors.initials: D
authors.lastname: Lev