Systematic discovery of novel angiogenic genes and a novel vascular disrupting agent

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2014-09-09

Authors

Cha, Hye Ji

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Abstract

Study of associations between genes and traits reveals a surprising depth to the evolutionary conservation of genetic modules. For example, a systematic analysis of such conserved modules showed that genes in yeast that maintain cell walls have been repurposed in vertebrates to regulate vein and artery growth. By analyzing this particular module, five novel genes that regulate angiogenesis were identified. These genes were specifically expressed in blood vessels, and I further characterized the role of several genes in vascular formation. On the basis of this remarkable modular repurposing, I reasoned that small molecules targeting the pathway in yeast might act as angiogenesis inhibitors suitable for chemotherapy. This insight led to the finding that thiabendazole, an orally available antifungal and antihelmintic drug in clinical use for 40 years, also potently inhibits angiogenesis in animal models and in human cells. Moreover, in vivo time-lapse imaging revealed that thiabendazole reversibly disassembles newly established blood vessels, marking it as a vascular disrupting agent and thus as a potential complementary therapeutic for use in combination with current anti-angiogenic therapies. Thiabendazole had a very slight effect on the organization of the microtubule, but significantly reduced the abundance of tubulin. Interestingly, it specifically targeted tight junction negative vessels, which suggests selective activity on the cells and tissues. Cellular structure of comet-like accumulation, formed by end-binding proteins at the distal tip of microtubules, was also significantly disrupted in the endothelial cell but not in the fibroblast. Multiple sequencing alignments of human tubulins with thiabendazole resistant fungal and worm tubulins implied that two specific human tubulin isotypes may be more susceptible to thiabendazole than other human tubulin isotypes. Indeed, time-lapse imaging of end-binding proteins revealed that one of the tubulin isotypes was more sensitive to thiabendazole than the others. Importantly, I also show that thiabendazole slows tumor growth and decreases vascular density in preclinical fibrosarcoma xenografts. Thus, an exploration of the evolutionary repurposing of gene networks has led directly to the identification of a potential new therapeutic application for an inexpensive drug that is already approved for clinical use in humans

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