Key Cancer Gene Discovered

Scientists identify gene that controls other cancer-causing genes

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HealthDay Reporter

WEDNESDAY, Jan. 19, 2005 (HealthDayNews) -- Cancer is caused by the activity of rogue genes that act like street toughs within cells, forcing them to multiply out of control. Now, scientists say they've identified a kind of "kingpin" gene that rules this gang of delinquent DNA.

"It's the 'leader of the pack,' and in that sense, it's a very effective target for therapy," said senior study author Dr. Pier Paolo Pandolfi, a pathologist at Memorial Sloan-Kettering Cancer Center in New York City.

Drugs to shut down the newly identified gene, which the researchers named POKEMON (for POK Erythroid Myeloid Ontogenic factor), could treat a wide spectrum of cancers, Pandolfi added, because other cancer-causing genes appear to lose their power when this key gene is switched off.

The findings are published in the Jan. 20 issue of Nature.

Most of today's cancer therapies focus on the targeted destruction of existing cancer cells. But what if the genes that cause cancer -- called oncogenes -- could be switched off before they had a chance to act?

Scientists have already identified a host of oncogenes responsible for specific cancers. However, Pandolfi's team hoped to find a gene impacting on a much wider range of malignancies.

Eventually, they narrowed their search to Pokemon, which occurs naturally in human cells and is actually beneficial when working properly.

"We all have a set of genes that controls the proliferation or survival of cells in the body, and these genes usually do this in a very harmonic way," Pandolfi explained. "For example, when we have an infection, the cells of our blood need to be told to proliferate, to counteract the infection."

Genes such as Pokemon are designed to do just that. However, when they malfunction, the result can be the uncontrolled cell growth of cancer.

To test whether Pokemon might play a role in directing other oncogenes, Pandolfi's team inserted a dysfunctional form of the gene into mice. As expected, all the mice quickly developed a fatal form of lymphoma.

The researchers then used genetic engineering to "knock out" the Pokemon gene in another group of mice. These mice failed to develop cancers of any kind. In a third experiment, tissues taken from a wide range of human tumors revealed the gene is expressed at very high levels in cancerous cells, regardless of the type of cancer involved. What's more, higher levels of the gene were associated with more aggressive cancers.

According to the Sloan-Kettering team, Pokemon appears to be strategically placed, effectively controlling a network of cancer-causing genes.

"The unique property of Pokemon is that it is doing this when it's overexpressed," Pandolfi said. "But when you take it out, remove its activity from the cell, then none of the other oncogenes in the cell are able to transform, to behave as oncogenes. In other words, Pokemon is essential for the activity of these other oncogenes."

The next step, he said, is to find drugs that can shut down Pokemon activity. Because his team already knows so much about the behavior of this gene, that shouldn't be difficult, he added.

"The beauty of Pokemon is that not only do we know that it's important, we know its specific biochemical activity," Pandolfi said.

Switching off genes such as Pokemon could come with risks, but the New York researcher believes this approach -- stopping cancer before it can start -- will prove far less toxic than standard therapy.

Surgery or conventional chemotherapy, no matter how targeted, "are clearly very toxic because there's no way you can avoid damaging the surrounding region," Pandolfi explained. "But with gene therapy, we are correcting the misbehavior of a specific cell type, going against the underlying molecular reason as to why the cells are proliferating. It's becoming apparent that this type of targeted intervention is much less toxic."

His team is also trying to identify those cancers in which Pokemon plays a direct role, and those in which its role is less immediate.

"Remember, though, that Pokemon doesn't have to be directly involved in causing this or that cancer" to be effective, Pandolfi said, since it controls the activity of so many other cancer-causing genes.

Even in malignancies where its role is less clear, the gene "should still be a very good target for therapy," he added.

More information

To learn more about the genetic causes of cancer, go to the American Cancer Society.

SOURCES: Pier Paolo Pandolfi, M.D., Ph.D., professor, cancer biology & genetics, Sloan-Kettering Institute, head, molecular and developmental biology lab, Cornell University Graduate School of Medical Sciences, and attending physician, department of pathology, Memorial Sloan-Kettering Cancer Center, New York City; Jan. 20, 2005, Nature

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