Vascular disrupting agents (VDAs) are an emerging class of therapeutics targeting the existing vascular network of solid tumors. However their clinical progression has been hampered due to limited single-agent efficacy, primarily due to the persistence of surviving cells at the well-perfused 'viable rim' of tumors, which allows rapid tumor regrowth to occur. In addition, off-target adverse events, including cardiovascular toxicities, underscore a need for compounds with improved safety profiles. Here we characterize the mechanism of action, antitumor efficacy and cardiovascular safety profile of STA-9584, a novel tubulin-binding VDA. In vitro, STA-9122 (active metabolite of STA-9584) displayed increased potency relative to other tubulin-binding agents and was highly cytotoxic to tumor cells. STA-9584 induced significant tumor regressions in prostate and breast xenograft models in vivo and, in an aggressive syngeneic model, demonstrated superior tumor growth inhibition and a positive therapeutic index relative to combretastatin A-4 phosphate (CA4P). Importantly, histological analysis revealed that STA-9584 disrupted microvasculature at both the center and periphery of tumors. Compared to CA4P, STA-9584 induced a 73% increase in central necrotic area, 77% decrease in microvasculature and 7-fold increase in tumor cell apoptosis in the remaining viable rim 24 hours post-treatment. Ultrasound imaging confirmed that STA-9584 rapidly and efficiently blocked blood flow in highly perfused tumor regions. Moreover, cardiovascular effects were evaluated in the Langendorff assay and telemetered dogs and cardiovascular toxicity was not predicted to be dose-limiting. This bioactivity profile distinguishes STA-9584 from the combretastatin class and identifies the compound as a promising new therapeutic VDA candidate.
- Received May 25, 2012.
- Revision received July 11, 2012.
- Accepted July 25, 2012.
- The American Society for Pharmacology and Experimental Therapeutics