Chemotherapy drug bortezomib packs a one-two punch

Feb 20 2007

Cancer can be wily, and those who treat the disease have amassed a wide array of weapons with which to fight it and kill tumors.

Radiation therapy and various forms of chemotherapy were all thought to be separate but equal treatments. Now, however, new research is beginning to show that it's not just killing the cancer cells that matter. How they're killed may turn out to be just as important and could play a role in marshalling the body's immune response.

New research by Rockefeller University associate professor Madhav Dhodapkar, head of the Laboratory of Tumor Immunology and Immunotherapy, shows that one form of chemotherapy - a drug called bortezomib - kills tumor cells in such a way that it may allow the immune system to recognize them. In a first edition paper published online this week by the journal Blood, Dhodapkar, postdoctoral fellow Radek Spisek, and their colleagues show that unlike radiation or other chemical therapies, bortezomib can kill multiple myeloma cells in culture in such a way that it elicits a response by memory and killer T cells. The results suggest the drug has the potential to enhance patients' immunity to tumors, helping their bodies fight the disease more effectively.

Multiple myeloma is a cancer of immune cells in the bone marrow. Dhodapkar's experiments show that when treated with bortezomib in tissue culture, multiple myeloma cells die in such a way that a heat shock protein, called hsp90, migrate to their surface. When another group of immune cells, called dendritic cells, encounter hsp90 on the dying tumor cells, the protein acts as a signal for their activation. The dendritic cells then ingest them for presentation to memory and killer T cells, a progression that - in humans - could potentially lead to enhanced immunity. "If you could directly target the drug to these cells," Dhodapkar says, "it may be sufficient enough to create a vaccine. The exposure of heat shock proteins on dying cells represents an immunogenic form of cell death."

When the researchers tested other standard treatments for multiple myeloma, such as radiation or the corticosteroid dexamethasone, the therapies failed to increase levels of hsp90 on the surface of dying cells, and so couldn't activate dendritic cells to the degree that bortezomib did. And their findings aren't limited to a single cancer: After treatment with bortezomib, dying lymphoma and breast cancer cells experienced the same increase in hsp90.

How well this research will translate to increased survival rates depends on how applicable these tissue culture studies are to the actual immune system response in people. So Dhodapkar plans to determine whether the enhanced T-cell effect he witnessed in tissue culture holds true in patients treated with this drug. If it does, the next move will be to directly target tumors in patients. "A simple experiment that hasn't been done yet is simply injecting bortezomib directly into tumors. By directly targeting the tumor, rather than injecting the drug intravenously, we may be able to take better advantage of bortezomib's distinct properties," he says.