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2004 Scientific Report

Takahashi, Masayuki,

Takahashi, Masayuki, Ximing J. Yang, Todd T. Lavery, Kyle A. Furge, Bart O. Williams, Maria Tretiakova, Anthony Montag, Nicholas J. Vogelzang, Gian G. Re, A. Julian Garvin, Stefan Söderhäll, Susumu Kagawa, Debra Hazel-Martin, Agneta Nordenskjöld, and Bin Tean Teh. 2002. Gene expression profiling of favorable histology Wilms tumors and its correlation with clinical features. Cancer Research 62(22): 6598–6605. From left to right: Furge, Dykema 28

Laboratory of Cancer Immunodiagnostics Brian B. Haab, Ph.D. Dr. Haab obtained his Ph.D. in chemistry from the University of California at Berkeley in 1998. He then served as a postdoctoral fellow in the laboratory of Patrick Brown in the Department of Biochemistry at Stanford University. Dr. Haab joined VARI as a Special Program Investigator in May 2000. Staff Muthu Shanmugam, Ph.D. Randall Orchekowski, B.S. Sara Forrester, B.S. Laboratory Members Visiting scientist Harvey Nikkel, Ph.D. Student Darren Hamelinck Research Interests T he Haab laboratory is developing and applying new technologies to meet the need for improved molecular diagnosis of cancer. Using antibody microarrays and related technologies, we are identifying changes of protein composition in the bodily fluids of cancer patients that can be used for new diagnostic tests and that give molecular information about the cancers. The research in our laboratory is broadly divided into three areas: 1) technology development; 2) pancreatic cancer studies; and 3) prostate cancer studies. Technology development We have been engaged in developing new antibody and protein microarray methods that enable parallel measurement of many different, specific proteins in biological samples. The experimental advantages of microarray technology include low consumption of reagents and samples, good reproducibility, high sensitivity, and the ability to efficiently run many samples. We have given great attention to establishing robust, reliable, and versatile protocols that are portable to other formats and to other laboratories. A recent collaboration with Paul Lizardi and others from Yale University resulted in the establishment of a new high-sensitivity detection method for antibody microarrays. This method, based on rolling-circle amplification (RCA), produces reproducible and significantly enhanced fluorescent signals from antibody microarrays, resulting in lower protein detection limits relative to previous methods. We also have developed robust methods for efficient, high-throughput processing of samples by printing multiple microarrays on a single microscope slide. This allows us to efficiently perform studies on the large sample sets that are necessary for clinical research. Future technology development plans include measuring the relative levels of post-translational modification (such as glycosylation or phosphorylation states) for the proteins captured by the arrays. The microarray format also provides unique opportunities to study the fundamental aspects of immunoassays, such as the relative merits of competitive and noncompetitive assays or the effects of various buffer additives or surfaces on protein stability and activity. Pancreatic cancer studies A major goal of the Haab laboratory is to develop serum biomarkers for the early and specific detection of pancreatic cancer. Most pancreatic cancers are detected at an advanced, untreatable stage, resulting in a five-year survival rate of less than 5%. Early detection, as would be enabled by a highly accurate blood test, would provide an excellent chance to improve survival rates. Until now, the development of a clinically useful blood test for early detection of pancreatic cancer has been elusive, despite the identification of many proteins with altered serum levels. A problem with the existing blood tests is that they are based on single proteins. Since there are significant molecular differences among tumors and among people, the blood level of any single protein is highly variable and usually not reliable for a clinical test. The antibody microarray method developed in our laboratory uses an alternative strategy: to develop blood tests based on the combined measurements of multiple proteins, which 29

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