Drug Fights Multiple Myeloma by Putting "Brakes" on Cell Proliferation

An experimental drug targeted to a cancer-causing mechanism within the cell may be a powerful weapon against deadly multiple myeloma.

So concludes a team of researchers at the Weill Medical College of Cornell University in New York City. They report their findings in the Aug. 1 issue of Cancer Research.

Animal studies using human myeloma cell lines show that the experimental agent - called PD 0332991, an orally active, small molecule - 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, professor of pathology and laboratory medicine, and professor of microbiology and immunology at Weill Cornell Medical College. That groundbreaking work was published last December 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."

And 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.

"Our work is really opening up a whole new target for drug development - not just for multiple myeloma, but potentially for all cancers," says study lead researcher Dr. Linda Baughn, a Leukemia and Lymphoma Society Fellow at Weill Cornell.

Multiple myeloma, found deep within the bone marrow, originates in cells called B lymphocytes. It is the second most common blood cancer, with more than 15,000 Americans diagnosed with the disease each year. Multiple myeloma is invariably fatal, with an average life expectancy after diagnosis of just three years.

"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. Luckily, researchers at the drug giant Pfizer, Inc., had already been busy developing just such an agent - PD 0332991.