A novel drug that blocks both the proteasome and aggresome protein-disposal systems in cells has shown such promise against drug-resistant multiple myeloma cells in culture that clinical trials are being planned, according to an article in the June 14th issue of the Proceedings of the National Academy of Sciences.

The goal of the current work had been to find a way to evade drug resistance to bortezomib (Velcade), which had been approved for use in the USA only two years ago. The novel agent is a combination of bortezomib (which blocks the proteasome system) and an experimental compound, tubacin, which blocks the aggresome protein-disposal system.

The combination agent proved to be more than twice as effective as either drug alone against drug-resistant cells taken from patients’ bone marrow.

“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 was Teru Hideshima, MD, also of Dana-Farber.

Bortezomib was the first in a class of proteasome inhibitors, which cause lethal stress in cancer cells by blocking the proteasome-based disposal mechanism. The accumulation of abnormal proteins triggers cell death.

However, many cancer cells are resistant to proteasome inhibitors like bortezomib. Recent studies have revealed an alternative protein-disposal complex, the aggresome, which might be sufficiently active in these cells to avoid cell death.
The American researchers designed a drug, tubacin, which 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.”