1GRU Cancer Center, Augusta, GA, USA, 2University of Cincinnati Cancer. Institute, Cincinnati ... European Society for Medical Oncology 2013. Published by ...
Annals of Oncology 24 (Supplement 1): i7–i17, 2013 doi:10.1093/annonc/mdt042.35
Lectures L08:02
NOV C-TER: A NOVEL VEGF-INDEPENDENT ANTI-ANGIOGENIC AGENT WITH A PROMISING PRECLINICAL ANTI-TUMOR EFFICACY
NOV (nephroblastoma overexpressed) C-Ter (NOV C-Ter) is the carboxy-terminal sequence (170 aa) of NOV/CCN3 (357 aa), the third member of CCN family. NOV/ CCN3 is secreted by vascular cells and is involved in angiogenesis through the regulation of various cell functions including proliferation, differentiation, survival, adhesion and migration. Here, we report the anti-angiogenesis and anti-tumor activities of NOV C-Ter. In vitro, NOV C-Ter inhibits endothelial cell tube formation on matrigel and tumor induced vascular network formation. Interestingly, when tested on HUVEC, NOV C-Ter appears to selectively inhibit SCHN2, apelin and adrenomedullin pathways, with a non-significant inhibitory effect on VEGF. Moreover, MAP Kinase and AKT phosphorylation are both decreased in HUVEC after exposure to NOV C-Ter (100 µg/ml). Interestingly, evaluation of NOV C-Ter using the NCI anticancer drug screen panel did not reveal a direct cytotoxic effect on epithelial cancer cell lines. In vivo, NOV C-Ter shows an anti-tumor activity in an orthotopic glioma model using human X-12 cells in two independent experiments. Nude mice (n = 10) received intracranial X-12 cells, followed by NOV C-Ter (i.v. injection), or PBS (i.v. injection), or bevacizumab (i.p. injection) treatment. NOV C-Ter provided a significant overall survival (OS) benefit over the control (PBS) and bevacizumab arms: the median OS were 100 and 152 days for PBS and bevacizumab groups respectively, while it was not reached after 186 days in the NOV C-Ter group. No significant difference in body weight was observed between the NOV C-Ter and the PBS control group. In summary, NOV C-Ter demonstrates anti-angiogenic and anti-tumor effects with a novel mechanism of action. We are planning to test this compound in a phase 1 clinical trial by 2014.
© European Society for Medical Oncology 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology and NDDO Education Foundation. All rights reserved.
abstracts
O. Rixe1, X. Qi2, Z. Chu2, J. Celerier3, L. Leconte3, N. Minet3, J. Pakradouni3, B. Kaur4, F. Cuttitta5 1 GRU Cancer Center, Augusta, GA, USA, 2University of Cincinnati Cancer Institute, Cincinnati, OH, USA, 3Sisene Biotechnology, Paris, France, 4Ohio State University, Columbus, OH, USA, 5National Cancer Institute, Gaithersburg, MD, USA
