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Researchers home in on genetic signature of esophageal cancer
Date:5/18/2011

he effect of oncogenes.

Prior studies on EAC had shown an extra copy of a DNA sequence in the 7q21 chromosome region. However, Godfrey and colleagues believe they are the first to map the region with fine enough resolution to identify six genes within the core of the amplified region, and to compare them to patient outcomes.

They further honed in on two genes, CDK6 and CDK4, and through laboratory experiments proved that both genes are critical for the growth of esophageal cancer cells.

Amin Ismail, Ph.D., the postdoctoral scientist in Godfrey's lab who led the research, explained that the two molecules appear to do exactly the same thing, however CDK4 is located elsewhere, in the 12q13 chromosome region, and although it is less frequently amplified compared to CDK6, its high expression in EAC may be attributed to other genetic alterations.

Researchers explored the activity of CDK4 and CDK6 both independently and in combination. They paid special attention to CDK6, which also has been associated with poor survival in T-cell lymphoma and two common brain cancers, gliomas and medulloblastomas. CDK6 is a known regulator of the cell cycle, and thus researchers theorized that if they could shut down the CDK6 activity, the proliferation of cancer should also cease.

These experiments, Ismail said, led to the discovery that CDK6 is not acting completely alone, and that the combined over-expression of CDK6/4 was a more accurate marker of poor survival than the amplification of either gene alone.

Meanwhile, researchers knew that an experimental drug (known as PD-0332991) targeting CDK6/4 had been developed by Pfizer and Onyx, and was already being used in early clinical trials, showing promise against a range of cancers.

Therefore, the Wilmot research team tested PD-0332991 in the laboratory on esophageal cancer cells and discovered that, indeed, the drug halted CDK6/4 by inhibiting the entire cell-cycle process
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Contact: Leslie Orr
leslie_orr@urmc.rochester.edu
585-275-5774
University of Rochester Medical Center
Source:Eurekalert

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