Abstract 5349: Angiotensin-(1-7) inhibits the growth of human pediatric rhabdomyosarcoma in a mouse xenograft model
Authors: Gallagher Patricia E. , Maglic Dino , Krishnan Bhavani , Castellino Sharon M. , Tallant E. Ann 
Published: June 2012

Pediatric sarcomas are rare tumors encompassing a diversity of histology and can arise in almost any part of the body. Despite overall advances in pediatric cancer treatment, outcomes in sarcomas have improved little in the past 2 decades. Based on the rarity of these tumors and the growing body of knowledge on late effects of conventional therapies in pediatric cancer survivors, it is imperative to develop new targeted agents for the treatment of these childhood diseases. In published studies, we showed that angiotensin-(1-7) [Ang-(1-7)], an endogenous seven amino acid peptide hormone, inhibited the proliferation of human lung cancer cells through activation of a unique AT(1-7) receptor and significantly reduced the size of human A549 lung tumor xenografts, in association with a decrease in the density of blood vessels and pro-angiogenic factors. These studies are in agreement with our Phase I clinical trial in which adult patients displaying clinical benefit had reduced circulating levels of the angiogenic factor PlGF; two of the four patients showing a clinical response to Ang-(1-7) had a primary sarcoma. The purpose of this study was to determine whether Ang-(1-7) may serve as a targeted chemotherapeutic agent for the treatment of pediatric sarcoma. Ang-(1-7) significantly inhibited the growth of A673 cells, a pediatric rhabdomyosarcoma cell line which expresses the AT(1-7) receptor mas. More importantly, the heptapeptide significantly reduced the proliferation of human A673 tumor xenograft growth in vivo. A673 rhabdomyosarcoma cells were injected into the flank of athymic male mice; the tumors grew to approximately 100 mm3 followed by infusion of saline or 24 µg/kg/h Ang-(1-7) for 18 days. The average volume of the tumors from mice treated with the heptapeptide was approximately 6-fold less than the size of the tumors from control animals (4770.6 ± 860.4 mm3 versus 664.8 ± 190.9 mm3; n = 6, p &lt; 0.001). In addition, Ang-(1-7) administration markedly reduced tumor weight, from 7.2 ± 1.5 g in the saline-treated mice to 2.2 ± 0.8 g in Ang-(1-7)-treated mice (n = 6, p &lt; 0.02). The decrease in tumor growth from Ang-(1-7)-medicated mice was associated with an approximate 50% reduction in immunoreactive Ki67, suggesting that the heptapeptide reduces tumor cell proliferation. Tumors from mice treated with Ang-(1-7) also showed a marked decrease in vessel density as assessed by CD34 immunoreactivity and morphology (7.6 ± 0.9 to 3.6 ± 0.6 vessels/per field, p &lt; 0.001), demonstrating that the observed reduction in tumor growth was due, in part, to inhibition of angiogenesis. These studies suggest that the heptapeptide has both anti-proliferative and anti-angiogenic properties and that Ang-(1-7) may be a new, first-in-class compound for the treatment of pediatric sarcoma targeting a specific AT(1-7) receptor mas.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5349. doi:10.1158/1538-7445.AM2011-5349