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Serum Proteomics Yield New Biomarkers for Ovarian Cancer

Johns Hopkins Kimmel Cancer Center researchers have designed a blood test to detect ovarian cancer using three proteins found in common in the blood of women with the disease. Their preliminary studies with the new test suggest a molecular signature exclusive to this deadly cancer, known for its ability to remain undetected and spread quickly. The Hopkins test, described in the August 15 issue of Cancer Research, identifies the proteins as a truncated form of transthyretin, a fragment of ITIH4 and apolipoprotein A1, teased out with a rigorous evaluation of protein patterns present in blood samples from ovarian cancer patients at several U.S. and international hospitals. Other research groups are evaluating ovarian cancer blood tests that use protein profiles consisting of tens of thousands of unidentified molecules. “By identifying a select group of biomarkers specific to ovarian cancer, we not only know the proteins we are dealing with, but we can trace them back to alterations in the genetic code of ovarian cancer cells,” says Daniel W. Chan, Ph.D., professor and director of the Biomarker Discovery Center at Johns Hopkins. “We are focusing on the markers for which we have good biological reasoning behind their selection, and hope to expand the panel of markers to catch as many variations in ovarian cancer proteins as possible.” This research was funded by the National Cancer Institute and Ciphergen Biosystems, which has licensed the test. Chan and his co-workers emphasize that the test will not be commercially available for screening the population at large until completion of further validation studies in larger groups of patients. And even then, Chan notes, it is never going to be possible for a blood test to correctly diagnose 100 percent of cancerous tumors 100 percent of the time. “The goal is to come as close as possible to that by using this test in combination with other available diagnostic tools.” They believe, however, that with some refinements it may already have use for helping determine whether a pelvic mass is ovarian cancer. In a systematic search to find the most promising blood proteins for their test, the Hopkins scientists conducted a multicenter study and used protein chip technology to screen a total of 195 blood samples from two groups of ovarian cancer patients, healthy people, and patients with benign ovarian tumors. A sophisticated bioinformatics program was used to select proteins present at unusually high or low levels in ovarian cancer samples as compared with normal or benign. Samples in the two groups were analyzed separately to account for differences in patient populations and sample collection techniques. Then, researchers compared protein profile results in these two groups and ultimately narrowed the search for potential marker candidates to the three proteins, one of which (ITIH4) is commonly found at high levels in ovarian cancer and the other two at lower levels. “Typically, only half of early-stage ovarian cancer patients have elevated blood levels of a standard marker called CA125,” says Zhen Zhang, Ph.D., associate professor and associate director of the Biomarker Discovery Center at Johns Hopkins. “By combining our discovered proteins into a multi-marker assay, it may improve detection of stage I/II ovarian cancer.” The new proteins were screened against a separate collection of blood samples from patients with normal and cancerous tissues. Of 23 patients with Stage I/II invasive ovarian cancer, the three protein markers alone and combine with CA125 correctly identified cancer 74 percent of the time (17 of 23) as compared to 65 percent (15 of 23) with CA125 alone. Although the sample size was too small for this difference to be statistically significant, the scientists conducted further studies lowering the cutoff value for CA125 to below current standards. The new test plus CA125 as well as CA125 alone detected 83 percent (19 of 23) of the cancers. In addition, the new test plus CA125 correctly identified healthy samples 94 percent of the time (59 of 63) as compared to 52 percent (33 of 63) for CA125 alone. To verify that the candidate markers were specific to ovarian cancer, the scientists also compared results of the protein profiles with a separate group of blood samples from 142 Johns Hopkins ovarian, breast, colon, prostate cancer patients and healthy people. Protein markers from Hopkins’ ovarian cancer samples matched those from the other two groups of blood samples. Breast, colon and prostate cancer samples exhibited levels of the three proteins closer to those of normal patients, indicating that the markers may be exclusive to ovarian cancer. The scientists will conduct further studies to map all three proteins to the genetic pathways linked to ovarian cancer development and combine the blood test with radiologic tools such as ultrasound. They also will search for more proteins to add to the current panel of markers. Additional research participants included Robert Bast Jr. and Yinhua Yu from the M.D. Anderson Cancer Center; Jinong Li, Lori Sokoll, Alex Rai, Jason Rosenzweig, Bonnie Cameron, and Young Wang from Johns Hopkins; Andrew Berchuck from Duke University Medical Center; Carolien van Haaften-Day and Neville Hacker from The Royal Hospital for Women, Australia; Henk de Bruij and Ate van der Zee from University Hospital Groningen, the Netherlands; Ian Jacobs from Bart’s and The London, Queen Mary’s School of Medicine, United Kingdom, and Eric Fung from Ciphergen Biosystems. Zhang, Z. et al, “Three Biomarkers Identified from Serum Proteomic Analysis for the Detection of Early Stage Ovarian Cancer,” Cancer Research 2004; 64. Under a licensing agreement between Ciphergen Biosystems, Inc. and the Johns Hopkins University, Chan is entitled to a share of royalty received by the University on sales of products described in this article. Chan is entitled to Ciphergen Biosystems, Inc. stock options, which is subject to certain restrictions under University policy. Chan also is a consultant to Ciphergen Biosystems, Inc. and a member of the company’s scientific advisory board. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies.