Fosbretabulin (DB12577): A Comprehensive Monograph on a Vascular-Disrupting Agent in Oncology

Executive Summary

Fosbretabulin, also known as Combretastatin A-4 Phosphate (CA4P), is an investigational small molecule drug that represents a distinct class of anticancer agents known as Vascular-Disrupting Agents (VDAs). Originating as a water-soluble prodrug of combretastatin A4, a natural compound from the African bush willow, Combretum caffrum, Fosbretabulin was engineered to overcome the pharmaceutical limitations of its parent compound. Its mechanism of action is both potent and unique, centered on a dual-pronged attack against the tumor vasculature. Primarily, its active metabolite, combretastatin A4, binds to the colchicine site of β-tubulin, leading to rapid depolymerization of the microtubule cytoskeleton in immature endothelial cells. This is complemented by a secondary mechanism involving the disruption of VE-cadherin-mediated cell junctions. The synergistic result is a swift and catastrophic collapse of tumor blood vessels, leading to acute ischemia and extensive necrosis within the tumor core.

Preclinical models demonstrated remarkable efficacy, with single doses causing near-total shutdown of tumor blood flow within hours. However, these studies also revealed a critical limitation: the survival of a peripheral "rim" of viable tumor cells, which invariably led to regrowth. This single observation has fundamentally shaped the drug's clinical development, mandating a strategic focus on combination therapies designed to target this surviving fraction.