A molecule that targets a cell’s mechanism for breaking down unneeded proteins can kill multiple myeloma cancer cells that have become resistant to bortezomib and other myeloma drugs, researchers at Dana-Farber Cancer Institute have found.
Lead investigator Dharminder Chauhan, PhD, described the research in an interview with Value-Based Care in Myeloma. The results of the study were recently published (Chauhan D, et al. Cancer Cell. 2012;22:345-358).
Dr Chauhan commented on the value of finding a means of overcoming resistance to what has become a go-to agent in myeloma. “New agents that can be added to our current arsenal of drugs and that would overcome resistance to current therapies would be very valuable. Bortezomib is successful in many patients, but it often loses its effectiveness over time, and this prompted us to seek other drug targets. Having drugs that could overcome resistance would provide hope for patients who have no response to current treatments,” he said.
P5091 Mechanism of Action
The small molecule P5091 (synthesized by Progenra) is part of a new class of compounds targeting the ubiquitin proteasome system. Dysfunction of the UPS has been linked to the development of many human diseases, including cancer, and is a valid target for therapy, according to the investigators.
The ubiquitin proteasome system is home to the proteasome, which rids cells of unwanted proteins, but this drug is not a proteasome inhibitor. “P5091 does not target the proteasome itself, but one specific enzyme upstream of the proteasome,” Dr Chauhan noted.
“The proteasome acts like a garbage disposal for the cell—chewing up and disposing of unwanted proteins. Inhibiting the proteasome with a drug like bortezomib causes an accumulation of waste proteins that spurs cancer-cell death,” he continued. “But the proteasome is a component of a bigger mechanism, the ubiquitin proteasome system. This system functions in 2 ways: it can attach small proteins known as “ubiquitins” to cell proteins, thus ticketing those proteins for disposal by the proteasome, or it can remove ubiquitins, thus sparing the proteins from disposal.”
The new compound is an inhibitor of the deubiquitylating enzyme USP7, which helps remove ubiquitin from proteins (ie, it is a “deubiquitylator”). USP7 regulates key biological signaling pathways in tumorigenesis, and its inhibition induces the arrest of tumor growth and cell death, even in cells resistant to conventional myeloma therapies (including bortezomib).
Studies of P5091
“Collectively, our studies utilized multiple myeloma cell lines, patient tumor cells, and myeloma xenograft models, as well as biochemical and genetic models, to show the antitumor activity of the USP7 deubiquitylating enzyme inhibitor P5091,” Dr Chauhan said.
P5091 was shown to trigger apoptosis (ie, cell death) in drug-resistant myeloma cells both in vitro and in animal models. In animal tumor model studies, P5091 not only inhibited tumor growth, but it prolonged survival and was well tolerated.
The study’s senior author, Kenneth C. Anderson, MD, Director of the Jerome Lipper Multiple Myeloma Center and the LeBow Institute for Myeloma Therapeutics at Dana-Farber Cancer Institute, Boston, described the effect in a September 12, 2012, press release. “In laboratory cell cultures, P5091 resulted in the death of myeloma cells. In animal models of myeloma, this molecule impaired tumor growth, prolonged survival, and didn’t harm normal tissue,” Dr Anderson said (www.dana-farber.org/Newsroom/News-Releases/Molecule-shows-effectiveness-against-drug-resistant-myeloma.aspx).
The drug’s ability to kill even myeloma cells resistant to standard therapies was also shown in cells from patients with myeloma.
The antimyeloma effect was even more powerful when P5091 was combined with other antimyeloma drugs, including lenalidomide, dexamethasone, and the histone deacetylase inhibitor SAHA.
The current research is a proof-of-concept study, and the compound has not yet been formulated into a drug. The findings, however, propel further development of the USP7 inhibitors, for which P5091 is the lead compound, according to Dr Chauhan.
He said the study shows 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. Our results lay the groundwork for testing USP7 inhibitors, either alone or in combination with other drugs, in patients with multiple myeloma.”