December 17, 2008
Gene Therapy Selectively Targets Cancer Cells

In a PNAS paper some U Rochester researchers report they've discovered a modified gene which expresses itself 5 times more in cancer cells than in regular cells.

Vera Gorbunova, assistant professor of biology at the University of Rochester, and her team, Andrei Seluanov, assistant professor of biology, and graduate student Christopher Hine, were investigating Rad51, a protein that is expressed at about five times higher level in cancer cells than in healthy cells, when they stumbled on something very unexpected.

Think of DNA as software. We need software that acts like a killer virus in cancer cells but which doesn't do anything harmful in regular cells. The ability to deliver a piece of software into a cell that can execute in a way that only kills cancer cells would put curing cancer within reach. This discovery is a useful step toward that capability.

"We stripped off some of the Rad51 gene and replaced it with a marker protein DNA to see why Rad51 was five times more abundant in cancer cells," says Gorbunova. "We wanted to see if there was any way we could boost that difference and create a really useful cancer-targeting tool. We couldn't believe it when we saw the cancer cells expressing the engineered Rad51 around a thousand times more."

When Gorbunova first saw the huge discrepancy, she thought one of her graduate students had fumbled the lab test. Further tests showed that the altered Rad51 was expressed in some cancer cells as much as 12,500 times as often as healthy cells, says Gorbunova. Such a large discrepancy means scientists should be able to use it to create versions of Rad51 that carry a "toxic bomb," which only the cancer cells will trigger.

Rad51 is normally involved in DNA repair, which explains why it's more often expressed in cancer cells. Cancer cells reproduce at accelerated rates, often "not stopping to fix their DNA when they should," says Gorbunova. In these cancer cells, Rad51 is working overtime to repair all the damage, so it's not surprising that it is expressed more often.

Gorbunova believes that when she stripped out part of the Rad51-coding gene, she also stripped out some regulatory elements, which control the production of the protein. Without these elements, healthy cells ignore the gene and do not make the protein. However, these changes have opposite the effect on cancer cells, causing elevated, uncontrolled protein production.

Given a gene that will get turned on much more in cancer cells it becomes possible to tack something toxic onto it to do far more damage in cancer cells than in normal cells.

Gobunova and her team have already fused a variant of diphtheria toxin into the Rad51 gene as a "toxic bomb" and tested it on a variety of cancer cell types, including breast cancer, fibrosarcoma, and cervical cancer cells. The results look very promising, she says.

To make a gene therapy against cancer capable of a cure we would need a way to deliver gene therapy into almost all cells or at least almost all cells in an organ or almost all cells of some type. Otherwise a few cancer cells will escape and continue replicating.

Share |      Randall Parker, 2008 December 17 11:00 PM  Biotech Cancer

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