Abstract 1938: Angiotensin-(1-7), a peptide hormone with therapeutic potential for the treatment of glioblastomas
Authors: Maria A. Garcia-Espinosa, Glenn J. Lesser, Waldemar Debinski, E. Ann Tallant, Patricia E. Gallagher
Journal: Cancer Research (2012)

Abstract Glioblastoma multiforme (GBM), the most common primary malignant brain tumor in adults, is characterized by aggressive proliferation throughout the brain parenchyma and enhanced angiogenesis. Despite multimodality treatment, GBM therapy is only palliative with a median patient survival of less than 10 to 12 months after diagnosis, indicating a need for novel agents with therapeutic potential. Angiotensin-(1-7) [Ang-(1-7)] is an endogenous, seven amino acid peptide hormone with anti-proliferative and anti-angiogenic properties which provides targeted therapy by activating mas, a unique G protein-coupled receptor. In this study, Ang-(1-7) effectively reduced the growth of human GBM in an orthotopic mouse model. Athymic mice with brain tumors resulting from injection of human G48a GBM cells, isolated from a grade 4 astrocytoma, were treated for 28 days with 24 μg/kg/h Ang-(1-7), delivered by osmotic mini-pump. The G48 GBM cells formed an aggressive and invasive phenotype, with outgrowths extending into the brain parenchyma. Ang-(1-7) administration markedly reduced the average tumor burden (a 75% reduction in tumor mass) as compared to untreated control mice (9.4 ± 1.6 x1010 vs 2.4 ± 1.3 x1010 p/sec/cm2/sr, p &amp;lt; 0.022). Histological analysis of brain tissue sections from untreated mice showed a significantly higher percent of Ki67 positive immunoreactivity in tumors as compared to tumor tissue from Ang-(1-7)-treated animals, suggesting that the heptapeptide hormone reduces cell proliferation. In support, proliferation of G48a cultured cells which express the mas receptor was reduced approximately 50% following incubation with 100 nM Ang-(1-7) for five days. Ang-(1-7) treatment also resulted in a marked decrease in MAP kinase ERK1/ERK2 phosphorylation with a concomitant 2-fold increase in the MAP kinase phosphatase DUSP1, suggesting that the heptapeptide hormone negatively regulates GBM cell growth in part by attenuating ERK1/ERK2 activation. Intratumoral vessel density in GBMs from mice administered Ang-(1-7) was attenuated more than 50% as compared to tumors from control animals. VEGF mRNA and protein were decreased over time with a maximal reduction at 8 h in G48a cells following treatment with 100 nM Ang-(1-7). Conversely, the soluble VEGF receptor sFlt-1 was significantly increased in cells incubated with the heptapeptide hormone. sFlt-1, produced by alternative mRNA splicing of Flt-1, is secreted into the circulation and serves as an endogenous trap that sequesters VEGF family ligands, making the angiogenic factors unavailable to the cell-bound VEGF receptors and preventing the downstream activation of pro-angiogenic signaling pathways. Taken together, these studies suggest that Ang-(1-7) inhibits the growth of aggressive, invasive GMBs by pleiotrophic mechanisms and may serve as a first-in-class, targeted, anti-proliferative, anti-angiogenic chemotherapeutic agent for GBM. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1938. doi:1538-7445.AM2012-1938