One of the more common experiments in cancer research is profiling the activity of genes in tumor cells. This reveals patterns of gene activity that can be used to search for potential drug targets.

But rarely has this approach led to a therapy. All too often, it seems, efforts are derailed because identifying a potential drug target from a tumor's genetic signature is difficult, expensive, and time consuming.

A team of researchers addressed this problem 2 years ago by developing a strategy that, in effect, skips the hard part. Rather than dissecting the signature, they suggest, use the signature as a tool for discovering cancer drugs.

"We asked whether a genetic signature itself could be the basis for screening drugs," Dr. Todd Golub of the Dana-Farber Cancer Institute said last week at the AACR annual meeting.

The idea is to identify drugs that can alter the entire genetic program of a cancer cell, allowing the cell to acquire the traits of a normal counterpart. So far, the strategy has apparently worked as planned.

Last year, the researchers used it to discover that gefitinib (Iressa) might be a potential treatment for acute myeloid leukemia (AML). A clinical trial is under way to test the drug in patients with relapsed or refractory cases of AML.

AML was the test case for the signature-based screen because patients with this disease have few treatment options. AML is too rare to attract the attention of most pharmaceutical companies, and new sources of potential drug targets are needed.

"The problem very often in trying to develop drugs is that we don't know the identity of the critical targets" for developing therapies, says Dr. Kimberly Stegmaier, who studies AML at Dana-Farber and helped create the screen.

But with the signature-based screen, no prior knowledge about the biology of the disease is needed. All that's required is the genetic signature of the biological state one is hoping to achieve.

A major problem in AML is that certain cells do not mature, or differentiate, into normal blood cells. Thus, Dr. Stegmaier identified a signature associated with differentiation and then screened for chemicals that could induce the signature in AML cells.

The screen included many FDA-approved drugs to increase the chances of finding new uses for drugs known to be safe. This could lead quickly to a clinical trial.

"One of the goals from the start has been to translate discoveries in the lab rapidly into clinical medicine," says Dr. Stegmaier.

The screen yielded a candidate, but the chemical had been abandoned in development and never turned into a drug. The researchers knew, however, that the chemical inhibits the epidermal growth factor receptor (EGFR) gene.

Dr. Stegmaier then screened another EGFR inhibitor, gefitinib, using cells from eight patients recently diagnosed with AML. Gefitinib induced differentiation in the majority of the samples.

Based largely on these results and the fact that 100,000 lung cancer patients have taken gefitinib safely, the researchers launched the clinical trial. By year's end, they expect to have 20 individuals enrolled in the phase II study.

Dr. Stegmaier cautions that it is still early and the drug might not be as effective in patients as it was in the laboratory.

An important question not necessarily answered by the screening strategy is: Why is a drug effective?

In the case of AML, the researchers do not yet know. They do know that in cells from AML patients, gefitinib is not hitting the target it had been developed for, EGFR. This gene is not even turned on in AML.

"Ironically, this is not how the drug works," says Dr. Stegmaier, noting that several recent studies have described the off-target effects of targeted therapies.

The researchers say they are working hard to identify the true target or targets of gefitinib in AML cells because this might allow them to develop more potent drugs.

"Clearly there are additional targets to be characterized," Dr. Golub said at AACR. "It's important to find and exploit those additional targets."

He has been asked about the decision to start clinical trials without understanding why a drug might be helping patients. His response is that it's an easy decision when the circumstances warrant it.

"If there is a safe drug, and there are patients in need, then let's move ahead with trials while trying to figure out the mechanism," said Dr. Golub.

By Edward R. Winstead