Researchers at Rush University Medical Center are exploring the use of autoantibodies as protein biomarkers for identifying women at increased risk of developing ovarian cancer.
In a study published last month in the online edition of Cancer Epidemiology, Biomarkers & Prevention, the scientists detected elevated levels of an antibody to mesothelin – a well-characterized ovarian cancer antigen – in the blood of infertile women, suggesting that this antibody might be useful in screening this population for heightened risk for the disease.
Epidemiological studies have shown that infertility is one of the leading risk factors for ovarian cancer, Judith Luborsky, a Rush professor and lead author on the study, told ProteoMonitor. Measuring anti-mesothelin antibody levels might offer a way to determine specifically which infertile women are at highest risk of developing the disease.
Mesothelin itself – though linked to ovarian cancer – has proven a poor biomarker "probably because the levels are too low to measure," Luborsky said. Autoantibodies produced as part of the body's immune response to the protein, however, are more abundant, making it possible for researchers to measure them even when mesothelin itself is present only in undetectable levels.
This advantage has led a number of parties, including biotech firms like Dortmund, Germany-based Protagen, and researchers investigating diseases like breast (PM 01/07/2011) and other cancers (PM 02/12/2010), to pursue autoantibodies as potential protein biomarkers.
As Thomas Kodadek, a Scripps Research Institute scientist studying autoantibodies linked to Alzheimer's, told ProteoMonitor in a January interview, "the adaptive immune response against an initiating antigen results in millions-fold amplification of the antibodies that recognize it," making the antibodies much easier to detect and measure than many typical protein biomarkers (PM 12/24/2011).
Additionally, he noted, because "antibodies are a lot more stable than most serum proteins, how you collect the sample [and] freeze it isn't terribly important. Whereas for the guys who are doing standard proteomics, that sort of stuff just plagues them."
In addition to taking an autoantibody-based approach, the Rush team's work differs from typical biomarker discovery efforts in that they looked at samples not from actual cancer patients but from subjects who are merely at high risk for the disease. The hope, Luborsky said, is that this approach will provide the researchers with a simpler physiological environment in which to identify potential protein markers.
The cancer biomarker field has been proceeding such that "you take people with the disease and ask what markers are associated with that disease," she said. "But cancer is very complicated, and there are a lot of different reactions going on, and the markers that people have discovered, after many, many, many dollars spent, tend only to identify late-stage cancers – which is what they're using to discover these markers."
"When [researchers] look at [autoantibodies] they do the same thing," she added. "They take the end-stage disease and ask about antibodies as an alternative to the straight protein or antigen. The problem is that the tumor is very busy altering immune response, and so people have looked at antibodies [as early-stage markers] but not very successfully. What we're saying is that we need to go and look much earlier."
In the study, the researchers obtained sera from 109 infertile women, 28 with ovarian cancer, 24 with benign ovarian cancers or cysts, and 152 healthy controls. Of the infertile women 23 had endometriosis, 17 had ovulatory dysfunction, 25 had premature ovarian failure, and 44 were unexplained.
The scientists detected the presence of mesothelin antibodies in 59 percent of the women with ovulatory dysfunction, 44 percent with ovarian failure, 25 percent with unexplained infertility, and 11 percent of the healthy controls. They found that women with endometriosis, which is also associated with a high risk for ovarian cancer, did not have mesothelin antibodies – a result, Luborsky said, that is perhaps due to the fact that endometriosis is associated with a different kind of ovarian cancer than the other types of infertility.
While these findings are most relevant to the use of mesothelin antibodies for risk-screening purposes, the researchers are now working to line up prospective samples that could be used to research their usefulness as early detection biomarkers.
"At this point, the antibody test would be [useful as] an additional risk factor" that physicians could use to identify patients they should monitor particularly closely, Luborsky said. "The next thing to do is find out what the changes are that actually signal when a tumor has started, and that would be the diagnostic test."
In addition to exploring antibodies to known ovarian cancer antigens like mesothelin, the Rush scientists are also investigating antibodies to antigens linked to infertility that they identified in an earlier study, Luborsky said.
"We've got about ten antigens that we're looking at, and there's a good indication that a group of those antigens is common between [high-risk] women and women with ovarian cancer," she said. The goal, she noted, is to improve the test's accuracy by expanding the number of antibodies included.
"When you do these assays, you make a cut-off as best you can, but it's not perfect," Luborsky said. "So what we really need is a panel that will give us higher sensitivity and specificity."
As part of this development process, the researchers are working with Bio-Rad to move the test from its current ELISA format to a Luminex bead platform, she said, noting that this would allow them to test multiple analytes more efficiently and could lead to improved sensitivity.
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