Velcade with Salubrinal

Velcade is a drug that was approved as the first line treatment for MM in June 2008, after having been used as a treatment for recurrences since 2003. However, many patients do not respond and among those that do, virtually all eventually experience a recurrence of the MM. Most cancer fatalities are caused by recurrences rather than the initial diagnosis.

The mechanism by which Velcade fights MM cells can also cause a cell to become dormant rather than die. Dr. Julio Aguirre-Ghiso's lab identified a response that protected the multiple myeloma cells from the Velcade and enabled some of them to become dormant. The scientists speculated that these dormant cells were responsible for the later recurrence. They demonstrated that simultaneous treatment with another drug, salubrinal, which has no effect on the survival of MM cells, still dramatically enhanced the impact of the Velcade, raising the proportion of cells killed from 50% to 90%. This is achieved by preventing the MM cells from reversing the signals changed by Velcade. Further, the use of salubrinal after treatment with Velcade eradicated the dormant cells surviving the initial therapy. Salubrinal is notable for its lack of toxicity in preclinical models.

Denis M. Schewe and Julio A. Aguirre-Ghiso Inhibition of eIFα Dephosphorylation Maximizes Bortezomib Efficiency and Eliminates Quiescent Multiple Myeloma Cells Surviving Proteasome Inhibitor Therapy Cancer Research, Feb. 2009; 69: 1545-1552.