A quick turnaround against resistance
By Richard Saltus
With the molecular knowledge they're gaining about cancer cells, Dana-Farber scientists have shown that they can rapidly devise counter-strategies when new drugs meet the resistance barrier.
A case in point: Bortezomib, a compound developed and tested at the Institute, has helped many patients experiencing relapses of late-stage multiple myeloma, a still incurable blood cancer. The drug won approval for sale two years ago under the name Velcade. But some patients failed to show a response from the beginning, and others who initially responded lost ground when the myeloma cells took evasive action.
The target of bortezomib is the "proteasome," a kind of cellular trash can for unwanted proteins. Bortezomib jams the mechanism, causing a backup of toxic proteins that eventually kill the cell. But a recently discovered alternate disposal device, the "aggresome," can take over for the blocked proteasomes and allow the cancer cell to survive, says Kenneth Anderson, MD, director of Dana-Farber's Jerome Lipper Center for Multiple Myeloma.
In early 2005, one of Anderson's DFCI colleagues, Teru Hideshima, MD, PhD, suggested counterattacking by blocking the aggresome with a different drug so that the cell once again couldn't get rid of its old proteins. Jay Bradner, MD, of Dana-Farber, working with Stuart Schreiber, PhD, at the Broad Institute of the Massachusetts Institute of Technology and Harvard University, developed a prototype drug, tubacin, which inhibits the aggresome pathway.
Only six months later, Anderson and Hideshima reported that tubacin combined with bortezomib was very effective in killing drug-resistant myeloma cells in the laboratory. The scientists are now rapidly developing analogs of tubacin to test with Velcade in clinical trials. Anderson says the proteasome-aggresome combined attack may turn out to be more than a way to outwit resistance: "It's a whole new approach in treating multiple myeloma."
