1.Phase I safety, pharmacokinetic and pharmacodynamic evaluation of the vascular disrupting agent ombrabulin (AVE8062) in patients with advanced solid tumors.
Sessa C1, Lorusso P, Tolcher A, Farace F, Lassau N, Delmonte A, Braghetti A, Bahleda R, Cohen P, Hospitel M, Veyrat-Follet C, Soria JC. Clin Cancer Res. 2013 Sep 1;19(17):4832-42. doi: 10.1158/1078-0432.CCR-13-0427. Epub 2013 Jul 5.
PURPOSE: The vascular disrupting agent ombrabulin rapidly reduces tumor blood flow and causes necrosis in vivo. A phase I dose-escalation study was designed to determine the recommended phase II dose (RP2D) of single-agent ombrabulin administered once every three weeks in patients with advanced solid malignancies.
2.New vascular disrupting agents in upper gastrointestinal malignancies.
Quatrale AE, Porcelli L, Gnoni A, Numico G, Paradiso A, Azzariti A1. Curr Med Chem. 2014;21(8):1039-49.
Antivascular approaches aim to cause rapid and catastrophic shutdown in the vascular function of the tumour, leading to extensive tumour cell death. Tumour vascular disrupting agents (VDAs) are a new class of cancer therapies that target the existing vasculature of tumours, taking advantage of the relative instability of tumour vasculature and its supporting structures. Treatment with VDAs induces a rapid collapse and regression of tumour vessels, with a consequent deprivation of blood and oxygen which leads to ischemic or hemorrhagic necrosis of the tumour. In this review, an overview of the most recently developed vascular disrupting agents is reported, focusing on the biological effects exerted by these compounds on endothelial cells and tumour vasculature, potentially effective in the treatment of several malignancies including upper gastrointestinal tumours. In particular, we have focused on the antimitotic agent combretastatin and its numerous synthetic analogues such as combretastatin A-4-phosphate, OXI4503, and AVE8062, and on the colchicine analogue ZD6126.
3.Ombrabulin plus cisplatin versus placebo plus cisplatin in patients with advanced soft-tissue sarcomas after failure of anthracycline and ifosfamide chemotherapy: a randomised, double-blind, placebo-controlled, phase 3 trial.
Blay JY1, Pápai Z2, Tolcher AW3, Italiano A4, Cupissol D5, López-Pousa A6, Chawla SP7, Bompas E8, Babovic N9, Penel N10, Isambert N11, Staddon AP12, Saâda-Bouzid E13, Santoro A14, Franke FA15, Cohen P16, Le-Guennec S16, Demetri GD17. Lancet Oncol. 2015 May;16(5):531-40. doi: 10.1016/S1470-2045(15)70102-6. Epub 2015 Apr 8.
BACKGROUND: Ombrabulin (AVE8062) disrupts the vasculature of established tumours and has shown preclinical synergistic anti-tumour activity when combined with cisplatin. In this phase 3 trial, we aimed to assess the efficacy and safety of ombrabulin plus cisplatin compared with placebo plus cisplatin in patients with advanced soft-tissue sarcomas.
4.Novel VEGF-independent strategies targeting tumor vasculature: clinical aspects.
Petrillo M1, Borriello M, Fuoco G, Legge F, Iannone V, Ferrandina G. Curr Pharm Des. 2012;18(19):2702-12.
In the last decades, the active research in the field of tumor angiogenesis has led to the development of a class of agents providing an effective inhibition of neo-vessel formation through the blockade of VEGF related pathways. More recently, the identification of other factors involved in tumor angiogenesis, such as platelet-derived growth factor, fibroblast growth factor and Angiopoietins has emphasized the need to develop agents targeting multiple pro-angiogenic pathways. Although contrasting data are currently available regarding the clinical efficacy of multikinase inhibitors, Sunitinib, Sorafenib and Pazopanib have displayed encouraging results, and have fuelled further evaluations. Moreover, definitive data are also eagerly awaited regarding the clinical role of angiopoietins inhibitors. On the other hand, the existence of morphological, functional and architectural differences between normal and tumor vasculature has provided solid basis for the development of a novel class of compounds, known as Vascular Disrupting Agents (VDAs) able to selectively disrupt existing tumor vessels.