C. Wilson Xu, Ph.D.
Member, Drug Development Program
Dr. Xu received his Ph.D. from Massey University, New Zealand in 1991. As a Human Frontier Science Program fellow, he completed his postdoctoral studies at the University of California - Los Angeles and Harvard Medical School from 1992-1998. He was a member of the faculty at the Memorial Sloan-Kettering Cancer Center and the Graduate School of Biomedical Sciences of Cornell University from 1998-2004. After his stint as a founder and CSO of ProteinLinks from 2004-2007, he joined the Nevada Cancer Institute in the end of 2007
Laboratory Members
Staff
Yasuyo Urasaki, Ph.D.
Masako Abe, Ph.D.
Current Research Interests
Novel technologies for cancer drug discovery
Although the sequencing of the human genome has raised great hope for a new era in the prevention and treatment of human diseases including cancer, the rate of drug discovery has been instead stagnated. This is in part due to the fact that an estimated 80% of key cancer targets are not "druggable" because only enzymatic targets are amenable to the conventional drug screening technologies. Most of these undruggable targets are frequently involved in protein-protein interactions in signal transduction pathways in human tumors. Therefore, development of innovative approaches to making and breaking protein-protein interactions has the potential to accelerate the drug discovery.
Development of both TetOFF- and TetON-based two-hybrid systems for high throughput target discovery and drug screen. Dr. Xu's laboratory has previously developed a highly robust and selective two-hybrid system, enabling his group to identify peptide aptamers that distinguish among Ras alleles differing by only one amino acid. Recently, Dr. Xu's laboratory has made a new generation of TetR-based two-hybrid systems that dramatically reduce both false positives and false negatives, and allow for selecting small molecules that disrupt protein-protein interactions. Using these technologies, Dr. Xu's laboratory plans to select small molecules that disrupt protein-protein interactions in tumorigenesis pathways
Development of high-density cell microarrays for understanding drug-gene interactions. To rapidly uncover cellular phenotypes of gene regulatory circuits, Dr. Xu's laboratory has developed high-density cell microarrays that allow phenotypic determinations of gene activities and drug targets on a genomic scale. His laboratory plans to manufacture cell microarrays to elucidate interactions between these cells and anti-cancer drugs and other anti-cancer agents. Such studies should shed light on both drug targets and cancer processes.
Peptide aptamers are protein-based recognition agents that consist of constrained combinatorial peptide libraries displayed on the surface of a scaffold protein. Dr. Xu's laboratory has identified peptide aptamers that directly target oncogenic Ras and disrupt Ras-mediated signal pathways. Mutant ras genes (H-ras, K-ras, and N-ras in codon 12, 13, or 61) are potent oncogenes that are found in about 30% of human tumors. Despite significant efforts by academic and industrial laboratories, specific reagents directly targeting Ras have not been discovered. To identify such specific Ras inhibitors, Dr. Xu's laboratory isolated peptide aptamers that interact with mutationally-activated Ras by using a selective two-bait two-hybrid system. These Ras peptide aptamers disrupt Ras/Raf interaction and inhibit the MAP kinase cascade. Currently, we plan to develop Ras peptide aptamers into therapeutic agents.
Chromatin biology in yeast and tumor cells
The ability to detect extracellular stimuli and respond appropriately is essential for all cellular functions. Compelling evidence indicates that post-translational modifications of nucleosomal histones such as acetylation, methylation and ubiquitination modulate chromatin architecture and thereby regulate transcription, DNA replication, repair and recombination in both normal and cancer cells. However, how histone modifications sense extracellular cues and coordinate the cellular responses to them is not well understood. Therefore, defining the signaling events to and from histone modifications represents an important advance in the field of signaling transduction and chromatin regulation.
To dissect signal pathways through histone modifications, we have used ubiquitinated histone H2B in yeast as a model system. Dr. Xu's laboratory discovered that carbohydrates, through glycolysis, are potent inducers for mono-ubiquitinated histone H2B in yeast. Mono-ubiquitinated H2B, in turn, controls a variety of metabolic genes. This is the first demonstration linking a histone modification to metabolism, thereby uncovering a novel signal pathway mediated by ubiquitinated histone H2B.
Reprogramming of somatic cells
Somatic cell reprogramming offers a new and exciting opportunity for generating patient-specific pluripotent stem cells for a variety of human diseases. Dr. Xu's laboratory is currently developing cell therapies for metabolic diseases (such as diabetes) using induced pluripotent stem cells.
