Fred Hutchinson Cancer Research Center
The overall aim of the research carried out in our lab is to identify new anticancer drugs. To accomplish this aim, we use a wide range of experimental techniques ranging from organic synthesis to genetic screens in model organisms and drug screens in human cell lines. We also use a number of experimental systems ranging from budding yeast to mammalian cell lines. A large part of our research involves drug screens. We have pursued two strategies for identifying new anticancer drugs. First, we have carried out screens in which we use the genetic context of the cancer cell as the drug target. We identify compounds that are selectively toxic to cells that contain the “cancer context” but are non-toxic to normal cells. This type of phenotypic approach does not depend on a precise knowledge and understanding of the biology of cancer cells, in fact, it does not require choosing a specific protein target and consequently, does not risk choosing the wrong target. An additional aspect of this approach is that we need to identify the molecular targets of our lead compounds. For this reason, we are also developing high throughput, genome-wide strategies for drug target identification. We have focused on compounds that target cells with defects in chromosome segregation and the checkpoint that normally protects cells from chromosome mis-segregation.
The second broad strategy is to use chemical genetics to find more specific anticancer drugs. Chemical genetics is a combination of traditional phenotype-based screens with modern tools for discovery of therapeutic agents. We have focused on eukaryotic NAD-dependent deacetylases, an enzyme class that plays key roles in stress and DNA damage responses as well as life span regulation in organisms ranging from baker’s yeast to humans. Using chemical genetics, we have identified a class of NAD-dependent deacetylase, or sirtuin, inhibitors and have used these compounds to discovery new functions of these enzymes as well as validate them as therapeutic targets.
Other projects in the lab include the study of genetic interactions of mismatch repair mutants with ribonucleotide reductase as a potential strategy for the identification of drugs for the treatment of tumors with mismatch repair defects.