Synthetic Protein Discovery May Yield Major Breakthroughs in Oncology Treatment

By Matthew Mahady
Published: Monday, May 24, 2010
Academic research is fueling tremendous strides in oncology and biotechnology. The Academy delivers the latest news on biotech and oncology research, providing a link between the clinical world of cancer care and the university researchers who are pushing the envelope of knowledge and discovery.




Medical College of Wisconsin

Researchers at the Medical College of Wisconsin in Milwaukee have announced a pending patent on a new synthetic version of a protein involved in some cancers and immune system diseases. The protein, dubbed CXCL12, is known as a chemokine. Chemokines help the immune system navigate toward optimal targets, regulating the movement of cells into tissues. They essentially act as homing beacons, recruiting white blood cells to infected or injured sites.

New information on the structure of CXCL12 was uncovered in laboratory research by Brian Volkman, PhD, an associate professor of biochemistry, Medical College of Wisconsin. Dr. Volkman’s findings were derived, in large part, from the work of Michael Dwinell, PhD, associate professor of microbiology and molecular genetics, Medical College of Wisconsin. In 2001, Dr. Dwinell was the one who inspired Dr. Volkman to look into the properties of CXCL12.

Dr. Dwinell established that CXCL12 and its target cellular receptor—CXCR4—play an important role in the migration of cancer cells to common sites of tumor formation, such as bone marrow, lymph nodes, and liver and lung tissue. Dr. Dwinell’s laboratory also established that CXCL12 expression is key to interfering with cancer progression. Previous research on CXCL12 structure failed to establish the mechanism by which the protein interacts with the CXCR4 receptor, and a crucial step in the spread of metastatic cancer remained poorly understood.

The current study, funded by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health, hoped to build on Dr. Dwinell’s research on the new inhibitor and gain insight into the mechanism of CXCL12. Dr. Volkman’s lab created a 3-dimensional model to show how the CXCL12 protein interacts with a portion of the CXCR4 receptor. To complete the molecular model binding CXCL12 to CXCR4, Dr. Volkman and colleagues discovered that it was necessary to link two CXCL12 molecules. In effect, this locked the protein into a form that could not be chemically separated—a dimer—but that could still bind to the CXCR4 receptor.

The locked protein behaved differently from the unlocked form. Normal CXCL12 proteins strongly induce cell migration, but the protein’s locked form resulted in absolutely no cells migrating. The investigators had discovered that CXCL12 could be converted into a protein that inhibits cell migration. “This was exciting because it was genuinely unexpected,” recalled Dr. Volkman. “It was the strongest suggestion yet that chemokine dimers might really be active participants in directing the migration of white blood cells and possibly other kinds of cells.”

According to Dr. Volkman, the next step is to establish whether the CXCL12 dimer is effective in stopping or slowing the spread of cancer. To this end, he is again looking to rely on Dr. Dwinell’s assistance and foundational knowledge. Dr. Dwinell filed an earlier patent application on the use of CXCL12 in limiting cancer progression.

“While we focused on understanding details of the molecular structure of CXCL12, Dr. Dwinell’s research group developed a sophisticated method for measuring breast cancer metastasis,” reported Dr. Volkman. “So we asked him to help us design experiments to find out if his CXCL12 dimer could interfere with the spread of cancer.”

Although it has not yet been established that the CXCL12 dimer will have the desired effect on cancer development, Dr. Volkman said it is clear the CXCL12 molecule has an important role to play in designing new cancer treatments and he hopes that “stable synthetic versions of CXCL12 will allow us to conduct proof-of-concept studies about cancer prevention.”

The updated findings from Dr. Volkman’s research were published in the most recent edition of Science Signaling, a new online journal issued by Science magazine. Christopher Veldkamp, PhD, a biochemistry graduate of the Medical College’s Graduate School of Biomedical Sciences, served as lead author for the study.


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