1) Drug efficacy.
Improving treatment efficacy is a major challenge for healthcare and biomedical research. With the rapidly improving understanding of the genomes and expression landscapes of human populations as well as those of cancer samples, significant opportunities lie in the rational design of personalized medicine that can maximally benefit individual patients. Using a high-performance screen system, we can apply genome-wide CRISPR screen techniques to systematically identify novel genetic events that cause resistance or hypersensitivity to more than 30 types of anticancer drugs. Such a platform can also be extended to immunosuppressants, antivirals, cholesterol-lowering drugs and other types of medicines, yielding new insights into their pharmacogenomics, as well as novel genes involved in the pathways modulated by these drugs.
2) Novel oncogenes and tumor suppressors.
Our group also study cancer genomes to identify novel cancer genes. Such efforts are based on analysis of the large number of cancer genomes deposited in common cancer database such as COSMIC. For example, we showed that based on the type of nucleotide changes and the sequences surrounding mutation sites, at nucleotide level different types of mutations are generated at tendencies that can vary by up to 400 folds. This means certain types of cancer-promoting mutations will only be observed in a small number of samples in cancer database, due to the high unlikeliness of generating the underlying nucleotide mutations. By factoring the “relative mutational difficulty” back in, we can pick up such kind of rare but cancer promoting mutations from the background. This leads to the discovery of potential cancer-promoting roles for many genes previously unnoticed in the cancer field. We also studied gene amplification & deletion status of more than 14,000 cancer samples, generating a high-resolution cancer gene amplification & deletion map, which indicated several novel oncogenes and tumor suppressors. We are currently studying candidate novel cancer genes identified by the above approaches.
3) Novel regulators of major signaling pathways. Cancer and many other types of diseases are caused by deregulation of major signaling pathways. We developed a platform that can rapidly test whether a candidate event alters any of 15 major signaling pathways, providing an efficient platform to deconvolute the mechanism of novel oncogenes and tumor suppressors, as well as for genes implicated in various types of inherited diseases. Such a platform can also efficiently employ genome-wide screen techniques to uncover novel components of major signaling pathways, which will lead to better understanding of human diseases and potentially novel drug targets.