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Overlooked drugs may be target for cancer

U. ROCHESTER (US) — New research not only offers a better understanding of the basic biology of leukemia, but also demonstrates a powerful strategy for drug discovery, scientists say.

University of Rochester Medical Center researchers believe they are the first to identify genes that underlie the growth of primitive leukemia stem cells—and then to use the new genetic signature to identify currently available drugs that selectively target the rogue cells.

Although it is too early to attach significance to the drug candidates, two possible matches popped up: a drug not yet approved by the Food and Drug Administration that is in development for breast cancer, and another experimental agent that had been identified earlier as an agent that targets leukemia cells.

First author John Ashton led the study, which was published this month in the journal Cell Stem Cell.

“Our work is both basic and translational, and is an example of a terrific collaboration,” says Craig Jordan, professor of medicine. “We were able to use the latest technology to expand very strong basic laboratory concepts and conduct an intriguing analysis that may yield new insights for treatments of leukemia.”

Jordan studies leukemia stem cells, which, unlike normal cells, renew uncontrollably and are believed to be the first cells at the root of malignancy.

He collaborated with Harmut (Hucky) Land and Helene McMurray, investigators in biomedical genetics at URMC, who study the principle that cancer evolves from a unique, interactive network of genes that are governed by a distinct set of rules.

In 2008 Land’s laboratory published a paper in Nature reporting on a pool of approximately 100 genes that cooperate to promote colon cancer. The Land laboratory coined the term CRG for “cooperation response genes,” to emphasize the special synergy controlling this pool of genes.

Land is professor and chair of the Department of Biomedical Genetics, and co-director of the Wilmot Cancer Center.

The identification of CRGs broadened the view of cancer, Jordan says. Historically, scientists would study the intricacies of one or two individual pathways in a vast network of alterations. With the advent of CRGs, however, researchers now have a better picture of the sub-populations of genes that dole out instructions to primitive cancer cells, like controls on a circuit board.

Depending on whether CRGs are turned off or on, patterns change and cancer either progresses or stops.

Leukemia is notoriously resistant to treatment, and thus it makes a good target for new therapies. Most relapses occur because modern therapies are not designed to attack at the biologically distinct stem-cell level and thus, residual cancer circulates in the bloodstream.

Using mouse models and human leukemia specimens, Jordan’s team found approximately 70 CRGs that played a role in growth and survival of both primitive leukemia cells and more mature leukemia cells. Knocking out expression of the CRGs in mice reduced leukemia growth.

With the newly identified CRG signature for leukemia, researchers then employed the Broad Institute’s Connectivity Map, a sophisticated genomics tool open to the public since 2007. CMAP catalogs hundreds of known drug compounds and allows researchers to search for drugs that mimic the genomic disease signatures.

Jordan’s group wondered if any drugs in the database could suppress or reverse the function of the CRGs that control leukemia growth. They identified the best candidates, and those were tested further in the lab.

“No one else has used the targeting of CRGs as criteria to look for drugs that might treat cancer,” Jordan says. “By using the CRG approach, we found drug compounds that might never have been selected, based on their documented mechanism of action.”

Although the Connectivity Map database does not contain every available drug in the world, Jordan says it is periodically updated. Meanwhile, his lab is conducting parallel studies to validate the latest findings. (In related research, Jordan also discovered a plant-based compound that destroyed leukemia stem cells in lab experiments; that drug is now undergoing a Phase 1 clinical trial.)

Funding was provided by the National Institutes of Health, New York State Stem Cell Foundation, Department of Defense, and a University of Rochester Hematology/Oncology training grant.

Source: University of Rochester

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