Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers Home In on Genetic Signature of Esophageal Cancer

19.05.2011
University of Rochester Medical Center researchers have pinpointed two genes that are amplified in the worst cases of esophageal cancer, providing data to support a new investigational treatment that targets those same genes.

The study, led by Tony Godfrey, Ph.D., a research associate professor of Surgery at the James P. Wilmot Cancer Center at URMC, was published by the journal Clinical Cancer Research. It explores the chromosomal abnormalities that influence poor survival rates of esophageal adenocarcinoma (EAC), the more common type of esophageal cancer which occurs at the junction of the stomach and esophagus.

Considered uncommon 20 years ago, the incidence of EAC has grown faster than any tumor type in the United States, Godfrey said. Health authorities believe high rates of obesity and gastroesophageal reflux disease (GERD) contribute to the rising numbers. And despite more awareness, early detection, and newer combinations of cancer therapies, overall survival of esophageal adenocarcinoma ranges from 70 percent to 80 percent for early-stage patients to only 5 percent to 20 percent for stage 3 or 4 patients. Since most cases are discovered when the cancer has already spread, EAC is often a devastating disease.

Expression of CDK6 gene in patient tissueUntil lately, the identification of gene targets for EAC had been limited by too few tissue samples and the inability of technology to provide a finely detailed map of gene mutations.

However, Godfrey’s lab was able to collect tumors samples from 116 EAC patients, and then use modern molecular analysis tools – microarray technology -- to investigate the DNA in the tissue. The goal was to study known chromosomal regions associated with EAC and look for subsets of genes involved in malignancy that might also be markers of poor survival.

Amin Ismail, Ph.D.A better understanding of genetic markers is important because many modern cancer drugs, known as “targeted therapies,” are designed to chemically inhibit or block the 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 involved in malignancy.

“Our data provide direct evidence that CDK6 and CDK4 are strong predictors of poor survival, and that targeting those molecules is a viable treatment option,” Godfrey said. “Although we still have more work to do, we are excited about the excellent progress in the effort to find better treatments for esophageal cancer.”

The approach used by Godfrey and his team follows a classic example of another success story in cancer research. Decades ago scientists discovered that the protein HER-2 (human epidermal growth factor receptor 2) is frequently amplified in some breast cancers, causing them to become more aggressive. They reasoned that a drug was needed to effectively interfere with the HER-2 gene. That drug, known as Herceptin, was developed and then approved by the U.S. Food and Drug Administration in 1998 and is widely used today to boost the life expectancy of thousands of women. Interestingly, some patients with EAC also take Herceptin, due to recent studies showing that HER-2 also is over-expressed in a subset of esophageal tumors.

The National Institutes of Health funded the URMC study.

Leslie Orr | EurekAlert!
Further information:
http://www.rochester.edu

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: In best circles: First integrated circuit from self-assembled polymer

For the first time, a team of researchers at the Max-Planck Institute (MPI) for Polymer Research in Mainz, Germany, has succeeded in making an integrated circuit (IC) from just a monolayer of a semiconducting polymer via a bottom-up, self-assembly approach.

In the self-assembly process, the semiconducting polymer arranges itself into an ordered monolayer in a transistor. The transistors are binary switches used...

Im Focus: Demonstration of a single molecule piezoelectric effect

Breakthrough provides a new concept of the design of molecular motors, sensors and electricity generators at nanoscale

Researchers from the Institute of Organic Chemistry and Biochemistry of the CAS (IOCB Prague), Institute of Physics of the CAS (IP CAS) and Palacký University...

Im Focus: Hybrid optics bring color imaging using ultrathin metalenses into focus

For photographers and scientists, lenses are lifesavers. They reflect and refract light, making possible the imaging systems that drive discovery through the microscope and preserve history through cameras.

But today's glass-based lenses are bulky and resist miniaturization. Next-generation technologies, such as ultrathin cameras or tiny microscopes, require...

Im Focus: Stem cell divisions in the adult brain seen for the first time

Scientists from the University of Zurich have succeeded for the first time in tracking individual stem cells and their neuronal progeny over months within the intact adult brain. This study sheds light on how new neurons are produced throughout life.

The generation of new nerve cells was once thought to taper off at the end of embryonic development. However, recent research has shown that the adult brain...

Im Focus: Interference as a new method for cooling quantum devices

Theoretical physicists propose to use negative interference to control heat flow in quantum devices. Study published in Physical Review Letters

Quantum computer parts are sensitive and need to be cooled to very low temperatures. Their tiny size makes them particularly susceptible to a temperature...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

2nd International Conference on High Temperature Shape Memory Alloys (HTSMAs)

15.02.2018 | Event News

Aachen DC Grid Summit 2018

13.02.2018 | Event News

How Global Climate Policy Can Learn from the Energy Transition

12.02.2018 | Event News

 
Latest News

Researchers invent tiny, light-powered wires to modulate brain's electrical signals

21.02.2018 | Life Sciences

The “Holy Grail” of peptide chemistry: Making peptide active agents available orally

21.02.2018 | Life Sciences

Atomic structure of ultrasound material not what anyone expected

21.02.2018 | Materials Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>