Abstract A64: Adenovirus-mediated NK4 gene therapy for malignant mesothelioma.

Malignant mesothelioma (MM) is a highly invasive and chemoresistant malignancy induced by asbestos fibers. Hepatocyte growth factor (HGF) and its receptor Met play a critical role in the pathogenesis of MM, and targeting HGF/Met signaling could be therapeutically important. NK4, a HGF antagonist and angiogenesis inhibitor, consists of the N-terminal hairpin domain and four kringle domains of the -chain of HGF. The therapeutic potential of NK4 has been demonstrated in several types of tumors. However the mechanisms by which NK4 inhibits tumor growth have not been well elucidated. In this study, we show that the NK4 adenovirus potently inhibits cell viability, invasiveness, migration, and spreading of human MM cells in vitro. Significantly, we demonstrated for the first time that NK4 reduced expression levels of stem cell markers as assessed by western blot analysis and inhibited self-renewal of MM stem cells as measured by spheroid formation assay. Furthermore, NK4 adenovirus had strong antitumor and anti-angiogenesis effects in two different mouse models of MM. These findings suggest that NK4 holds promise as a therapeutic agent for patients with MM. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A64.