In a series of basic science experiments, researchers discovered a protein, GRP-78, that is responsible for resistance to Velcade ^[1] (bortezomib) treatment in some solid tumor cancers. The study was published in the journal Blood last Thursday.

Perhaps one reason why Velcade is especially effective in treating multiple myeloma is because myeloma cells do not secrete GRP-78. Nevertheless, some people with multiple myeloma are resistant to Velcade treatment. This research, besides finding important knowledge about a variety of cancers that do form solid tumors, may help scientists eliminate one possible cause of Velcade resistance in multiple myeloma.

Researchers at the Innsbruck Medical University in Austria hypothesized that some solid tumor cells secrete something that protects them from dying from Velcade’s effects. They performed a series of experiments to find this protective molecule and found GRP-78. They then tested GRP-78 to see how it interfered with Velcade.

To begin their experiments, they transferred different kinds of tumor cells into developing chicks and some human cells harvested from umbilical cords. They treated the chick embryos and human cells with Velcade.

To determine if the treatment was working, they looked at blood vessel growth in the tumors. Several recent studies showed that one of the ways Velcade works against cancer is by preventing blood vessels from growing in tumors, starving the tumor cells of blood.

Some cancers responded to the treatment and some did not:

• Velcade treatment did not work for colorectal carcinoma, melanoma, or prostate carcinoma, because Velcade’s action on blood vessels was blocked
• Velcade treatment worked for multiple myeloma, breast cancer, and glioblastoma, because Velcade’s action prevented blood vessel growth

To find out what might make certain cancer cells resistant to Velcade, the researchers blended and separated the Velcade-resistant colorectal carcinoma cells into their component parts: proteins, fluids, and more. They tested each of these components by adding them to some human embryonic cells, along with Velcade, to see which of these components blocked Velcade’s action on blood vessels.

They found that the only component that blocked Velcade’s action was the protein GRP-78.

By blending and separating other cells, they determined that though many cells contain GRP-78, including non-resistant cancer cells and normal human embryonic cells, resistant cancer cells have extra high levels of the protein.

To confirm GRP-78’s resistant activity, researchers added it to the non-resistant multiple myeloma cells. They then tried to treat those cells with Velcade. The treatment did not work, suggesting that GRP-78 conferred Velcade resistance to the previously non-resistant myeloma cells.

Next, they removed GRP-78 from resistant cancer cells and treated those cells with Velcade. The treatment worked. The researchers concluded that without GRP-78, previously Velcade-resistant cells lost their resistance, so GRP-78 must be responsible for Velcade resistance.

Lastly, the researchers performed some experiments to find out how GRP-78 interferes with Velcade. When cells treated with Velcade sense that they contain abnormal proteins and are deprived of blood, they begin to die. However, the researchers found that GRP-78 prevents cellular death. The researchers identified the pathway GRP-78 uses to prevent cellular death and suggested further studies on administering certain other proteins alongside Velcade in cancer treatments, to help counter resistance.

Meanwhile, the molecular basis of Velcade resistance in multiple myeloma remains “elusive,” according to a 2008 study ^[2] (abstract) published in the journal Blood. Recent studies have discovered some genes and proteins involved, however. These include studies published in the Journal of Clinical Oncology ^[3] (abstract) in 2009, in Oncogene ^[4] (abstract) in 2005, and the 2008 Blood paper. In 2008, Blood also published a review ^[5] of science’s current understanding of Velcade resistance.

Scientists hope that by discovering what causes Velcade resistance, perhaps in experiments similar to the Innsbruck Medical University’s GRP-78 study, they can develop treatments to overcome it.

Please see the article in the journal Blood for more information on the GRP-78 study ^[6] (abstract).