Abstract 3066: Anti-angiogenic properties of PM060184

Abstract

Abstract Vascular supply of tumors is one of the main targets for cancer therapy. Different studies have shown that most of the microtubule-binding agents present antiangiogenic and vascular-disrupting effects. PM060184 is a new marine-derived drug that binds to a new site in β-tubulin inhibiting tubulin polymerization. The compound is currently being evaluated in phase 1/2 studies in patients with advanced malignancies. The present study describes the antiangiogenic and vascular-disrupting properties of PM060184. Treatment of HUVEC endothelial cells with PM060184 resulted in depolymerization of the microtubule network. Differently from untreated cells, PM060184-treated cells showed a rounded morphology with a well-developed actin filament structure and plasma membrane blebs. Using transwell chambers pre-coated with matrigel™ or collagen matrix, we showed that PM060184 inhibited migration and invasion of HUVEC endothelial cells. We finally found that PM060184 interfered with the correct formation of the HUVEC capillary network grown on matrigel™; moreover, drug treatment also resulted in a significant disruption of the previously formed capillary-like network. This rapid collapse of the endothelial tubular network in vitro occurred in a concentration-dependent manner and was observed at concentrations lower than those affecting cells survival. These in vitro findings were confirmed in nude mice bearing MDA-MB-231 (breast) xenografts: after the administration of a single dose of PM060184 (at its MTD, 16 mg/kg,) a very strong reduction in the number of vessels was quantified in serial tumor sections stained with H&E. Moreover, nude mice xenografted with H-460 (NSCLC) tumors and treated with a single dose of either 2 or 16 mg/kg of PM060184, experienced a strong and dose-dependent decrease of the intratumoral fluorescence after the administration of Angiosense™ 680, a fluorescence vascular imaging probe. Altogether, these data suggest that an anti-vascular mechanism is also contributing to the anti-tumor activities of PM060184. Citation Format: Carlos M. Galmarini, Maria J. Guillen, Juan F. Martinez-Leal, Marta Martinez-Diez, Pablo Aviles. Anti-angiogenic properties of PM060184. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3066.