Novel Combination Overcomes Drug-resistant Myeloma Cells

Highly encouraged by the findings, the researchers hope to move rapidly to clinical trials of the therapy, a combination of the drug Velcade and an experimental compound that was designed by researchers at the Broad Institute of Massachusetts Institute of Technology and Harvard University.

The report, which will be posted online this week by the Proceedings of the National Academy of Sciences (http://www.pnas.org/papbyrecent.shtml), demonstrates that the combination was more than twice as effective as either drug alone in killing resistant cells from patients' bone marrow.

The promise is particularly exciting, scientists say, because many patients don't respond to Velcade, a drug approved just two years ago that's been an important new therapy for multiple myeloma, a disease which caused an estimated 11,000 deaths in 2004, according to the Multiple Myeloma Research Foundation.

"This is not just another drug, this is a whole new approach to treating multiple myeloma," said Kenneth Anderson, MD, senior author of the paper, whose lead author is Teru Hideshima, MD, also of Dana-Farber. Others include Stuart L. Schreiber, PhD, of Harvard University and the Broad Institute, and Jay Bradner, MD, of Dana-Farber and the Broad Institute.

Velcade is the first in a class of so-called proteasome inhibitors, which cause lethal stress in cancer cells by blocking the proteasome, a disposal mechanism that rids the cell of abnormal proteins. Cells in which the proteasome is jammed eventually commit suicide, triggered by the accumulation of proteins, explains Anderson, who is also the Kraft Family Professor of Medicine at Harvard Medical School.

However, many cancer cells are resistant to proteasome inhibitors like Velcade. Recent studies have revealed an alternative protein-disposal complex, the aggresome, that may take over enough of the job when the proteasome falters to allow the cells to survive.

Therefore, the Dana-Farber researchers suggested that blocking both protein disposals at once might get around this resistance mechanism. Scientists led by Schreiber at the Broad Institute designed a drug, tubacin, that blocks histone deacetylase 6, an enzyme that is critical to the aggresome's ability to function.

These highly promising results, wrote the researchers, "provide the framework for clinical trials designed to enhance sensitivity and overcome resistance to bortezomib [Velcade], thereby improving patient outcome in multiple myeloma."

The research was supported in part by grants from the National Institutes of Health, the Doris Duke Charitable Foundation, and the Multiple Myeloma Research Foundation.

Dana-Farber Cancer Institute is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), a designated comprehensive cancer center by the National Cancer Institute.