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Biomarkers in the Blood


Finding the hallmarks of cancer in blood is hard to do — cancer-related proteins are present only in small amounts, are difficult to sort from all of the other circulating proteins, and tend to be eliminated quickly by the body. But one group has devised a method that could turn that around. At the Technion-Israel Institute of Technology in Haifa, Arie Admon and his team have devised a method that combines immunoaffinity purification, microcapillary chromatography, and mass spectrometry to separate enough of these protein biomarkers to effectively diagnose blood cancers, including leukemias and multiple myelomas.

The method involves detecting human leukocyte antigens in the blood and analyzing them to see which kinds of peptides are attached. HLA molecules "ferry peptides from inside the cell to the cell surface," Admon says.

Once the peptides are anchored to the cell surface, T cells check to see whether the peptides are normal or not. Normal cells release a small amount of HLAs into the bloodstream, but cancer cells release larger amounts — which slows down and confuses T cells. Admon and his team discovered that not only are peptides from cancerous cells being released to the cell surface and into the bloodstream, but that HLA molecules are still bound to those peptides. "It's like a memory of a protein in the blood," Admon says. "And with our new method, we can actually purify these HLA molecules from the blood and get enough material to purify the peptides that are bound to these molecules."

After drawing a small amount of blood from a cancer patient, Admon and his postdoc Michal Bassani-Sternberg — who devised the method and was first author of the study published in PNAS in October — used immunoaffinity purification methods, passing the plasma through a column covalently bound with antibodies that attract HLA molecules. Once they washed the column to remove serum proteins, Admon and Bassani-Sternberg injected the peptides into an Orbitrap mass spectrometer to identify them. They were able to identify thousands of HLA peptides, some of which were cancer related, including tumor testis antigens, embryonic cancer antigens, and tumor-associated protein products. According to Admon, another advantage of this method is that immunoaffinity purification of the HLA molecules and their bound peptides provides researchers with an enrichment of five orders of magnitude of the biomarkers in the blood serum. The number of HLA molecules in the blood no longer matters, nor does the noise created by the other proteins in the blood.

The usefulness of the peptides as cancer biomarkers is not yet entirely clear, Admon notes. Although much work remains to be done, he is optimistic about this method's potential in the clinic. "We think it's going to be a universal method for finding cancer and other diseases," he says. Before that can happen, however, the same research has to be repeated in large cohorts of patients and in healthy control subjects. Admon and his team are continuing their work and expanding beyond multiple myelomas and leukemias. The growing ubiquity — and falling cost — of mass spectrometry analysis could help make the team's approach like this a common diagnostic test. "I envision it as a routine blood test, something rather simple," Admon says. "But until it's implemented in the clinic, there's still a lot more work to do.

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