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A combination with Bortezomib overcomes drug-resistant myeloma cells

A novel strategy devised by Dana-Farber Cancer Institute scientists has proved highly effective in killing drug-resistant multiple myeloma cells in the laboratory.

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

The report has demonstrated that the combination was more than twice as effective as either drug alone in killing resistant cells from patients’ bone marrow.

Many patients don’t respond to Velcade, a drug approved just two years ago that’s been an important new therapy for multiple myeloma.

Multiple myeloma is a disease which caused an estimated 11,000 deaths in 2004, according to the Multiple Myeloma Research Foundation.

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 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, thereby improving patient outcome in multiple myeloma.”

Source: Dana-Farber Cancer Institute , 2005