New Discovery in Zebrafish may Expedite Cancer Drug Development
Western University of Health Sciences College of Veterinary Medicine Assistant Professor Jijun Hao, PhD, discovered a novel compound that may offer leads for cancer therapy.
The findings are reported in a research paper titled “Selective Small Molecule Targeting ß-Catenin Function Discovered by In Vivo Chemical Genetic Screen,” published Sept. 5, 2013 in the prestigious Cell Press Journal Cell Reports, http://dx.doi.org/10.1016/j.celrep.2013.07.047.
Aberrant activation of the Wnt/β-catenin signaling is involved in numerous cancer types, including gastrointestinal cancer. Therapeutic agents that disrupt this signaling pathway are highly sought after by cancer experts.
“Despite intensive research, unfortunately, no drugs are currently available to block this pathway,” Hao said. “This publication reports one of only a few identified compounds that disrupt this pathway.”
By knowing the Wnt/β-catenin signaling involved in early embryonic development of zebrafish, Hao and colleagues at Vanderbilt University designed a phenotype-based screen to search for compounds that can disrupt fish dorso-ventral patterning, which is mediated by Wnt/β-catenin signaling.
“Such compounds would be selective inhibitors of this critical signaling pathway,” Hao said.
After screening thousands of compounds, Hao discovered a novel compound, Windorphen, that selectively blocks the Wnt/β-catenin signaling. Additionally, Windorphen robustly and selectively kills cancer cells that harbor Wnt-activating mutations, supporting the therapeutic potential of this novel Wnt inhibitor class.
“Zebrafish phenotype-based drug screening has many advantages over the traditional ‘target-based’ drug discovery approach,” Hao said.
The traditional ‘target-based’ drug discovery approach involves in vitro biochemical and cell-based assays, followed by in vivo animal tests and clinical trials. Because the initial in vitro screening does not take into account in vivo drug properties such as absorption, distribution, metabolism, excretion and toxicity, many drug hits identified in early in vitro screenings fail at the level of animal testing.
“This is why it takes about 15 years and costs about $2 billion before a new drug reaches market,” Hao said. “In contrast, zebrafish-based live animal screen could circumvent these pitfalls at the early time of drug development, and thus may significantly lower the costs and speed up drug discovery.”
Dr. Hao is a pioneer in zebrafish-based chemical screening. In the past, he has discovered several highly selective and bioactive chemical modulators of the key signaling pathways including DMH1 that has been widely used as a gold standard BMP inhibitor in scientific research. The compounds identified from his whole animal screening are generally less toxic, highly selective, bioactive and effective in multiple animal models, suggesting that the zebrafish phenotype-based approach is an efficient way for drug development.
Hao will continue his research at WesternU using zebrafish-based chemical study to search for more drug candidates.
