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Genomic Assay to Identify Targets of Anticancer Therapeutics

Institution: Stanford University
Investigator(s): Nolan Ko, Ph.D.
Award Cycle: 2008 (Cycle 17) Grant #: 17FT-0056 Award: $70,076
Subject Area: Cancer
Award Type: Postdoctoral Fellowship Awards
Abstracts

Initial Award Abstract
Cancer is a complex and deadly disease involving the transformation of normal cells into cells with uncontrolled cell divisions. Among cancer types, lung cancer is the most common among men and second most among women, and the number one cause of this deadly disease around the world is the use of tobacco. Numerous studies have shown that cigarette smoking and secondhand smoking account for more than 90% of all lung cancer cases. In addition, lung cancer is one of the top causes of tobacco-related death, thus treating and curing lung cancer is highly relevant to the fight against tobacco.

In recent years, to combat against lung and other cancers, much effort has been devoted to uncover new anticancer therapeutics and drugs, with special attention paid to natural compounds. Although many natural compounds have now been reported to inhibit cancer cell growth, the exact mechanisms behind their inhibitions often remain largely undefined at the molecular level. Two of these poorly understood compounds are diallyl disulfide in garlic and falcarinol in carrots. Several studies have shown that these compounds can inhibit various stages of tumor development in different cancer cell types, including that of lung cancer. Because of their anticancer potentials, it is important to figure out how exactly do they kill cancer cells, and the overall aim of the proposed research is to do precisely that.

More specifically, I will start out by using a modern yeast-based genomic assay to identify the putative molecular targets of the two natural anticancer compounds. I will then verify the identified targets with several follow-up experiments in yeast, human, and lung cancer cells. Finally, once the molecular mechanisms of the two compounds are determined, I will extend the results to study how small DNA variations in the human genome might alter the anticancer properties of the compounds.

The proposed work is highly relevant to the understanding of cancer and anticancer therapeutics. Not only will it help to develop new technology for studying and treating lung and other cancers, it will specifically shed light on the anticancer properties of two natural compounds. Furthermore, by also relating my results to small human genome variations, I will help to explain why various human populations respond differently to the same therapeutics. Finally, the proposed work will contribute immensely to the understanding of cancer, help the fight against tobacco, and yield great benefits to human health in general.
Publications

The AmesTest Redux: Using yeast genomics to identify toxin targers.
Periodical: Yeast Genetics & Molecular Biology Index Medicus:
Authors: Ko, N, St. Onge, R.; Ballew, A; Berens, T; Nislow, C.; Giaever, G.; Davis, R.; & Stearns,T ABS
Yr: Vol: Nbr: Abs: 464B Pg:

Testing single-nucleotide polymorphisms with humanized yeast. Annual Meeting Dec. 13-17, 2008, San Francisco, CA
Periodical: American Society for Cell Biology Index Medicus:
Authors: Ko, N.; Tam, J.; and Stearns, T. ABS
Yr: Vol: Nbr: Abs: 1281 Pg: