Grant: Project Grant

Cancer cells often overexpress specific genes due to the effect of translocations, gene amplification, or other epigenetic modifications. Researchers have thought that directly inhibiting the function of these overexpressing genes could help to eliminate cancer cells. For example, a gene called Polo-like kinase 1 (PLK1) is overexpressed in multiple cancers including colorectal cancers, indicating that inhibition of this kinase could be a powerful antitumor strategy. However, efforts to inhibit this kinase showed low objective response rates, poor survival and severe toxic side effects in clinical studies. This is because these drugs were not specific enough and often resulted in off-target effects, where they targeted other members of the polo-like family. To circumvent this concern, here we propose to take advantage of a basic biological concept called "Synthetic Dosage Lethality", where cancer cells overexpressing genes like PLK1 could be killed, when another gene is turned "OFF". In other words, rather than directly inhibiting genes like PLK1, we have developed a method that can query every single gene in the genome, in a span of four weeks, and identify those target genes whose loss-of-function can selectively kill PLK1-overexpressing cancer cells. Using this approach, we will execute our investigation in colon cancer cells as it ranks third in morbidity among all other malignancies. In addition, our lab is fully equipped with all the tools and reagents required to test the effect of the target genes that we identify in this cancer. Thus the successful completion of our project has the potential to identify several new druggable targets for colon cancer treatment. Our findings are expected to trigger the development of novel targeted therapies that would improve the survival of colon cancer patients.