Reverse Translation of Phase I Biomarker Findings Links the Activity of Angiotensin-(1-7) to Repression of Hypoxia Inducible Factor-1α in Vascular Sarcomas

Overview

Journal BMC Cancer

Publisher Biomed Central

Specialty Oncology

Date 2012 Sep 12

PMID 22963500

Citations 8

Authors

W Jeffrey Petty

Mebea Aklilu

Victor A Varela

James Lovato

Paul D Savage

Antonius A Miller

Affiliations

Soon will be listed here.

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.

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