In the Cancer Cell study, researchers tested whether P5091, a small molecule inhibitor of USP7 that was synthesized by Progenra, Inc., could cause the death of myeloma cell that had developed resistance to Velcade and other current therapies.
"Blocking USP7 decreases the level of a cancer-promoting protein called HDM2, which has the effect of bolstering p53 and p21, a gene that suppresses tumor cell growth," Chauhan states. "The result is that tumor cells stop growing and begin to die."
"In laboratory cell cultures, P5091 resulted in the death of myeloma cells," said the study's senior author, Kenneth Anderson, MD, director of the Jerome Lipper Multiple Myeloma Center and the LeBow Institute for Myeloma Therapeutics at Dana-Farber. "In animal models of myeloma, this molecule impaired tumor growth, prolonged survival, and didn't harm normal tissue." When researchers combined P5091 with the drugs lenalidomide, SAHA, or dexamethasone, the myeloma-killing effects were even more pronounced.
Although P5091 itself has not been formulated into a drug, the study demonstrates "that you can target molecules in the ubiquitin proteasome system without targeting the proteasome itself and still achieve a cancer cell-killing effect, with no significant toxicity," Chauhan remarks. "Our results lay the groundwork for testing USP7 inhibitors, either alone or in combination with other drugs, in patients with multiple myeloma."
Based on the study results, Progenra plans to help lead studies of USP7 inhibitors in future clinical trials.
|Contact: Bill Schaller|
Dana-Farber Cancer Institute