Stress response proteins offer a promising target for a novel drug guidance system

Sep 21 2004

Stress response proteins present on the outside of cancer cells offer a promising target for a novel drug "guidance system," say researchers at The University of Texas M. D. Anderson Cancer Center.

Their study, published in the September issue of the journal Cancer Cell, demonstrates how researchers can find protein tags that are unique to cancer cells and then tweak a drug delivery system to zero in on those tags and destroy the cells.

In this case, the strategy worked on breast and prostate cancer cell lines in animal models and in patient-derived samples in the laboratory, say the researchers, who add that they plan to test it next in human tumors.

"It's been very effective so far, and we think targeting this protein might also work in other tumor types," says Renata Pasqualini, Ph.D., a professor of Medicine and Cancer Biology at M. D. Anderson. "But, of course, we won't know that until we can test it in patients."

The advance builds upon the work of both Pasqualini and Wadih Arap, M.D., Ph.D., also a professor of Medicine and Cancer Biology at M. D. Anderson, who have jointly pioneered the "zip code" approach to designing drugs. They search for proteins that are specific to different tissue sites, or "addresses," within the body, which can then be used as drug targets.

This study, led by Pasqualini and Arap, evolved from a recent finding in their laboratory. Published in Nature Biotechnology in 2003, they reported that a protein in prostate cancer cells seems to be correlated with poor prognosis and advanced disease.

The protein was identified as glucose-regulated protein-78 (GRP78), which is part of a large family of "stress response proteins" that appear when a cell is in trouble. That stress could be due to a number of problems, ranging from chemotherapy or radiation damage to the low oxygen levels typical of cancer development, says Arap. "These stress proteins do many things that give cells a better fighting chance to survive, such as chaperoning misfolded proteins that arise under stress for destruction as needed," he says. "And the more stress a tumor cell is under, the more stress response proteins are produced."

Most researchers, including Arap and Pasqualini, believed these stress response proteins were found exclusively inside cells. That made sense because when the cell died and fell apart, these proteins, now released into the bloodstream, could elicit antibodies that could be correlated to disease stage in prostate cancer. But in this new work, it became clear to the researchers that the GRP78 proteins were actually being anchored in the cell membrane and presented on the outside of cancer cells for recognition. They say that raises the intriguing possibility that GRP78 surface expression could function as a signal to the immune system that help was needed.

"This is a major finding, because it means that the protein could be accessible to a drug that is designed to stick onto it," says Arap. "It is much easier to target a protein on the outside of a cell than to send drugs into the cell."

The team fashioned a drug that could "dock" onto the protein. The drug consisted of a ligand - a sequence of an amino acid that fit precisely onto the protein like a key into a lock - that was fused onto a corkscrew-shaped drug that the researchers knew could induce a cell to self-destruct.

They tested the drug on both prostate and breast cancer cells in the laboratory, and then in animals who had been implanted with human cancer cells of these types. "It worked in these tests and we also showed that it could bind to human tumor tissue," says Pasqualini.

"Breast cancer and prostate cancer share one important feature - they both metastasize to the bone marrow," says Pasqualini. "We hope that further studies will allow us to show that this therapy may be particularly active against metastatic disease."

"Together, these preclinical data validate GRP78 on the tumor cell surface as a potentially relevant molecular target that could prove useful for translational applications," says Arap.

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