Abstract A02: Nucleolin antagonist peptide N6L, normalizes tumor vasculature by decreasing Ang-2 secretion and inhibits pancreatic ductal adenocarcinoma growth and metastasis
Authors: Gilles Maud-Emmanuelle , Maione Federica , Carpentier Gilles , Destouches damien , Courty José , Giraudo Enrico , Cascone Ilaria 
Published: December 2015

Nucleolin (NCL) is a nucleolar protein regulating ribogenesis and cell cycle progression, and is overexpressed in tumor cells. Shuttling to the cell surface of tumor cells and tumor vessels NCL is a marker of tumor tissues and a target for cancer therapy. Recently, we developed a family of nucleolin antagonist pseudopeptides (NucANT). The N6L peptide, strongly inhibits human tumor growth by inducing apoptosis of tumor cells (1), and is currently in clinical trial for cancer. Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human malignancies, and an explanation of the failure of treatments is that chemotherapies are poorly delivered to the tumor because of a deficient and pathologic vasculature. We investigated the possibility that N6L could dually target tumor cells and tumor vasculature and be a promising new option for the treatment of PDAC.

NCL targeting by N6L inhibited pancreatic tumor cell proliferation and pancreatic tumor cell motility similarly to other tumor cell types (1). Concerning endothelial cells (EC), N6L inhibited EC proliferation, motility, adhesion and tubulogenesis. We screened proteins involved in vascular stability and showed that N6L treatment or NCL depletion regulated the secretion of Ang-2. This N6L effect was specific of NCL targeting because NCL depletion rescued the inhibition of Ang-2 secretion induced by N6L.

We investigated the effect of N6L on the growth and metastasis of a PDAC orthotopic mouse model that was deficient in vasculature such as the human tumors and NCL was highly expressed in tumor ductal epithelial cells. We showed that N6L strongly inhibited the tumor growth by inhibiting NCL expression, tumor cell proliferation, and increasing tumor cell apoptosis. Coherently with the in vitro data, N6L decreased Ang-2 plasma concentration of PDAC mice. By characterizing the PDAC tumor vasculature after treatment, we demonstrated that N6L induced both vessel pruning and normalization of tumor vasculature by improving pericyte coverage and tumor blood vessel perfusion. Moreover, N6L-induced tumor vessel normalization was accompanied by an improved efficiency of chemotherapeutic drugs delivery to cancer tissues and an inhibition of liver metastasis incidence.

We conclude that NCL inhibition by N6L normalizes pancreatic tumor vasculature and suggest Ang-2 as a target and a biomarker of N6L response. N6L-induced PDAC vessel normalization promotes drug delivery and contributes to decrease metastasis formation.

1. Destouches D, et al. (2011) A simple approach to cancer therapy afforded by multivalent pseudopeptides that target cell-surface nucleoproteins. Cancer Res 71(9):3296-3305.

Citation Format: Maud-Emmanuelle Gilles, Federica Maione, Gilles Carpentier, damien Destouches, José Courty, Enrico Giraudo, Ilaria Cascone. Nucleolin antagonist peptide N6L, normalizes tumor vasculature by decreasing Ang-2 secretion and inhibits pancreatic ductal adenocarcinoma growth and metastasis. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers; Mar 5-8, 2015; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl):Abstract nr A02.