Weill Cornell team Identifies Trigger for Relapse

Here's a wonderful Christmas present for Myeloma patients.
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Cyclin-Kinase Pairing Is Crucial to Oncogenesis

Findings Point to New Drug Targets

NEW YORK (December 23, 2005) — In a breakthrough discovery, researchers at Weill Medical College of Cornell University believe they have pinpointed the mechanism that triggers relapse in patients with deadly multiple myeloma.

While available drugs can push the disease into temporary remission, fatal, uncontrolled cell division always re-emerges over time. Until now, the cellular mechanism driving this relapse has remained unclear.

"We found that specific pairings of cell-cycle regulators — proteins called cyclins and enzymes called kinases — are necessary to drive myeloma cells toward that state of uncontrolled cell division, a hallmark of cancer," explained senior researcher Dr. Selina Chen-Kiang, Professor of Pathology and Laboratory Medicine, and Professor of Microbiology and Immunology at Weill Cornell Medical College.

"This discovery runs counter to the previous dogma that the overexpression of a particular cyclin, called cyclin D1, was all that was needed to trigger the overproliferation of myeloma cells," added co-lead researcher Dr. Scott Ely, Associate Professor of Clinical Pathology and Laboratory Medicine at Weill Cornell.

Instead, the researchers found that cyclin D1 or a related regulatory protein, cyclin D2, must first pair up with specific kinase enzymes — called CDK 4 and CDK6 — to drive myeloma cells toward division.

"It's as if the cyclin molecule is the gas, and the enzyme is the engine. You need both to get the car going," Dr. Chen-Kiang said. "Now that we think we understand this relationship, we have a whole new opportunity to target drugs toward these enzymes, giving new hope for more effective treatments."

The findings were presented at this month's annual meeting of the American Society of Hematology, and are also published in the December 15 issue of Cancer Research.

Multiple myeloma originates deep in the bone marrow and is the second most common blood cancer. The disease is always 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 explained.

Research continues as to why these myeloma cells don't undergo programmed cell death (apoptosis) as they should. But the Weill Cornell team focused on the other side of the cancer paradigm: Why these cells suddenly begin dividing uncontrollably.

Using bone marrow myeloma cells freshly isolated from patients and tumor cell lines obtained from end-stage patients, they discovered that this overproliferation hinges on specific cyclin-kinase relationships that govern cell cycling. These pairings appear to be mutually exclusive.

"For example, cyclin D1 pairs up with the enzyme CDK4, or cyclin D2 pairs up with CDK6 — but when we examined the cells, the two pairings never occurred together," said co-lead researcher Dr. Maurizio Di Liberto, Assistant Research Professor of Pathology and Laboratory Medicine at Weill Cornell.

The cyclin D2/CDK6 combo was particularly deadly, the team found.

"All of the cell lines that we obtained from terminal, end-stage patients showed this pairing," said Dr. Chen-Kiang. "That's exciting, because it suggests that we might be able to use the presence or absence of these biochemical pairings as prognostic indicators, which would help guide treatment."

She believes the findings should also overturn the old notion that the chromosomal translocation (and resultant overexpression) of cyclin D1 was the prime mover behind multiple myeloma.

"It never made sense to me — it was like having the gas without the engine," Dr. Chen-Kiang said. "Studies in Europe even found that patients with translocated cyclin D1 did better than patients without this translocation, giving us another reason to assume there was more going on there than meets the eye."

The finding could also have implications beyond multiple myeloma.

"It illuminates the complexity of how cancer arises," Dr. Ely said. "This finding is unprecedented in any cancer, and might apply to other malignancies — people just haven't looked at this hard enough before."

According to Dr. Chen-Kiang, finding compounds that target CDK4 and CDK6 are obvious next steps in the search for more effective treatments against multiple myeloma.

"It's still early," she said, "but a better understanding of how relapse occurs means that someday we may be able to prevent it from occurring at all."

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

Co-researchers included Dr. Ruben Niesvizky, Dr. Linda B. Baughn, Dr. Hearn J. Cho, Dr. Eunice N. Hatada, Dr. Daniel M. Knowles, and Dr. Joseph Lane — all of Weill Cornell Medical College in New York City.

Source: http://global.med.cornell.edu/news/wcmc/wcmc_2005/12_23_05.shtml