title: Reverse translation of phase I biomarker findings links the activity of angiotensin-(1-7) to repression of hypoxia inducible factor-1α in vascular sarcomas.
abstract: BACKGROUND
  In a phase I study of angiotensin-(1-7) [Ang-(1-7)], clinical benefit was associated with reduction in plasma placental growth factor (PlGF) concentrations. The current study examines Ang-(1-7) induced changes in biomarkers according to cancer type and investigates mechanisms of action engaged in vitro.
  
  
  METHODS
  Plasma biomarkers were measured prior to Ang-(1-7) administration as well as 1, 2, 3, 4, and 6 hours after treatment. Tests for interaction were performed to determine the impact of cancer type on angiogenic hormone levels. If a positive interaction was detected, treatment-induced biomarker changes for individual cancer types were assessed. To investigate mechanisms of action, in vitro growth assays were performed using a murine endothelioma cell line (EOMA). PCR arrays were performed to identify and statistically validate genes that were altered by Ang-(1-7) treatment in these cells.
  
  
  RESULTS
  Tests for interaction controlled for dose cohort and clinical response indicated a significant impact of cancer type on post-treatment VEGF and PlGF levels. Following treatment, PlGF levels decreased over time in patients with sarcoma (P = .007). Treatment of EOMA cells with increasing doses of Ang-(1-7) led to significant growth suppression at doses as low as 100 nM. PCR arrays identified 18 genes that appeared to have altered expression after Ang-(1-7) treatment. Replicate analyses confirmed significant changes in 8 genes including reduction in PlGF (P = .04) and hypoxia inducible factor 1α (HIF-1α) expression (P < .001).
  
  
  CONCLUSIONS
  Ang-(1-7) has clinical and pre-clinical activity for vascular sarcomas that is linked to reduced HIF-1α and PlGF expression.
authors.affiliation: Department of Medicine, Section on Hematology and Oncology, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC 27157, USA. wpetty@wfubmc.edu
authors.forename: W Jeffrey
authors.initials: WJ
authors.lastname: Petty
authors.forename: Mebea
authors.initials: M
authors.lastname: Aklilu
authors.forename: Victor A
authors.initials: VA
authors.lastname: Varela
authors.forename: James
authors.initials: J
authors.lastname: Lovato
authors.forename: Paul D
authors.initials: PD
authors.lastname: Savage
authors.forename: Antonius A
authors.initials: AA
authors.lastname: Miller
mesh_terms: D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000803:Angiotensin I / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D049109:Cell Proliferation; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009383:Neoplasms, Vascular Tissue / Q000378:metabolism*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012509:Sarcoma / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C000608036:PGF protein, human; D010446:Peptide Fragments; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D000072483:Placenta Growth Factor; D000803:Angiotensin I; C118790:angiotensin I (1-7)