Novel combination overcomes drug-resistant myeloma cells

Tubacin, an experimental compound created at the Broad Institute, overcomes the resistance of myeloma cells to the drug Velcade when both are administered together. In fact, the combination is more than twice as effective as either drug alone in killing resistant cells from patients' bone marrow. Encouraged by these laboratory findings, the scientists hope to move rapidly to clinical trials of this novel combination therapy.

"This is not just another drug, this is a whole new approach to treating multiple myeloma," said Kenneth Anderson, MD, of the Dana-Farber Cancer Institute and lead scientist of the study.

These findings are particularly exciting because many patients don't respond at all to Velcade, a drug approved just two years ago as an important new therapy for multiple myeloma. According to the Multiple Myeloma Research Foundation, the disease caused an estimated 11,000 deaths in 2004 alone.

"By combining this compound with a currently available chemotherapy agent, we have dramatically increased the anti-cancer effect," said author Jay Bradner, MD, who is a member of Broad's Chemical Biology Program and also of Dana-Farber.

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.

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 predicted that blocking both protein disposals at once might get around this resistance mechanism.

Scientists in the Broad Chemical Biology Program, directed by Stuart Schreiber, had recently discovered just such an aggresome inhibitor they named "tubacin." The collaboration born out of discussions between the Dana-Farber and Broad researchers led to this breakthrough discovery.

The results of this study will be published in the June 14, 2005 issue of the Proceedings of the National Academy of Sciences. In the manuscript, the researchers note that these results "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.

Adapted from a release by Dana-Farber Cancer Institute

Paper(s) cited

Hideshima T, Bradner J, Wong J, Dharminder C, Richardson P, Schreiber SL, Anderson KC. Small molecule inhibition of proteasome and aggresome function induces synergistic anti-tumor activity in multiple myeloma. Proc Natl Acad Sci U S A. 2005;102(24):8567-72. DOI:10.1073/pnas.0503221102.