New drug PD 0332991

A team of researchers at Weill Medical College, Cornell University in New York City report an experimental drug targeted to a cancer-causing mechanism within the cell may be a powerful weapon against multiple myeloma.

PD 0332991 is an orally active, small molecule which inhibits specific enzymes and proteins that dysregulate the cell's division and expansion.

"Previous work in our lab showed that when these kinase enzymes -- Cdk4 or Cdk6 -- inappropriately match up with regulatory proteins called cyclin D1 or D2, you get the uncontrolled proliferation of cells that is a hallmark of myeloma relapse," explains senior researcher Dr. Selina Chen-Kiang of Weill Cornell Medical College. That research was published in December, 2005 in Cancer Research.

Either combination -- Cdk4/cyclin D1 or Cdk6/cyclin D2 -- is like "adding gas to an engine," she explains. "Now, what we've found is a pharmacologic ‘brake' that stops the myeloma motor, cold."

Because these enzyme-cyclin pairings can help trigger the proliferation of cancer cells in general, inhibitors like PD 0332991 might prove useful in treating a wide range of tumors.

"There are drugs that are geared to getting people into remission, but they ultimately fail because there are still cancer cells that have the potential for self-renewal -- they'll rise again and start dividing," Dr. Chen-Kiang explains.

Her lab's discovery last year of just how relapse occurs was a real breakthrough. The "sequel," Dr. Chen-Kiang says, was to find an agent that could stop it.

"We knew what we were looking for: a pill whose active agent was a molecule small enough that it could get deep inside the myeloma cell," adds co-lead researcher Dr. Maurizio Di Liberto, assistant research professor of pathology and laboratory medicine at Weill Cornell. "The drug also had to be highly targeted -- it had to stop the proliferation of myeloma cells without harming normal cells," he said. Researchers at the drug giant Pfizer, Inc., had already been busy developing just such an agent -- PD 0332991.

PD 0332991 effectively prevented the growth of myeloma tumors in mice. The drug appeared to inhibit Cdk4 and Cdk6 in a way that was proportional to the proliferating state of the cell. The greater the combined negative effect of Cdk4 and Cdk6, the more PD 0332991 inhibited it.

"We noted that PD 0332991, by itself, does not induce apoptosis -- the death of existing cancer cells," Dr. Chen-Kiang explains. "So we wondered if combining it with other agents might help."

The team coupled PD 0332991 with dexamethasone, a drug commonly used against multiple myeloma.

"Using these two drugs together seemed to have a synergistic effect. We observed markedly enhanced killing of myeloma cells, even though we used one-tenth the dose of dexamethasone that's usually delivered to patients," Dr. Chen-Kiang reports.

The researchers are hopeful that combining PD 0332991 with other chemotherapies will be equally or more effective. Early data suggest that this approach will bring equally impressive results.

The advent of a mechanism-specific agent that stops multiple myeloma in its tracks is both unique and exciting, the research team says.

"It's controlling the disease by controlling the mechanism of myeloma cells' division," Dr. Baughn explains. "We've never had anything like this before."

"Scientists have known for a long time that Cdk4 and Cdk6 play key roles in the proliferation of nearly all cancer cell types, but until now we haven't found an agent that specifically targets only those two enzymes," she says.

"We're confident that if this works in myeloma, it should work in a wide range of other tumors, too," she says.

This study was funded by grants from the National Institutes of Health and the Leukemia and Lymphoma Society.

See also http://myelomic.blogspot.com/2005/12/weill-cornell-team-identifies-trigger.html