HARVARD GAZETTE ARCHIVES
Chemical screening technique holds drug discovery promise
New model rapidly screens hundreds of possible treatments
By Alvin Powell
Harvard News Office
Harvard researchers identified eight chemicals that induce a change in leukemia cells out of more than 1,700 candidates in a trial of a process they say holds promise as a way to rapidly identify potential drug candidates.
Kimberly Stegmaier, an instructor in pediatrics at Harvard Medical School and a pediatric hematologist-oncologist at the Dana-Farber Cancer Institute and at Children's Hospital Boston, said she and colleagues were hoping to find a way to rapidly screen chemicals for potential therapeutic value in diseases where current screening approaches are limited.
Acute mylogenous leukemia (AML), the most common form of leukemia afflicting adults, is such a disease.
AML affects white blood cells, which multiply rapidly but fail to mature. These immature, nonfunctional cells accumulate in the bone marrow, eventually crowding out healthy cells and resulting in anemia, easy bruising and bleeding, and impaired immune function.
Current treatment for AML involves chemotherapy to kill all the cancerous cells. But even with the procedure, the five-year survival rate among children - with whom Stegmaier works - is just 50 percent. Among adults, the disease is even deadlier. Its overall survival rate is just 18.7 percent, according to statistics from The Leukemia and Lymphoma Society.
"There's clearly a clinical need for better therapies for this disease," said Stegmaier.
But another treatment strategy might work.
A rare subtype of AML is treated with a drug that doesn't immediately kill the cancerous cells. Instead, it induces them to continue maturing into white blood cells. This therapy, combined with traditional chemotherapy, results in an 80 percent survival rate.
Unfortunately, that drug does not have the same effect on other AML subtypes. But Stegmaier said it's possible that a compound could be found to kick-start these cancerous AML cells in a similar way, inducing them to continue to mature into white blood cells.
Mechanisms poorly understood
A leukemia cell's development into a mature cell is a complex process that is poorly understood. That makes current drug screening methods, which target known cellular processes or which look for obvious physical changes, such as killing a cancerous cell, inappropriate.
"We don't really understand the whole process of differentiation, so we don't know what to target," Stegmaier said.
Rather than waiting for years until scientific understanding illuminates how AML cells can be induced to develop into mature cells, Stegmaier and colleagues decided to cut to the chase.
Instead of seeking a detailed understanding of the mechanisms involved, they decided to just treat leukemia cells with a wide range of chemicals and examine whether the desired change occurred.
"We can find chemical modulators of different [cellular] states without really knowing the mechanism involved in transitioning from one state to another," Stegmaier said.
They did this by examining the AML cell's RNA and comparing it with the RNA of a healthy white blood cell. They noted which genes were active in the white blood cell but not in the leukemia cell.
Armed with this information, they treated 1,739 samples containing leukemia cells with different chemicals and then looked at the cells' RNA. They found eight samples whose gene expression patterns had changed to match that of a normal white blood cell.
Stegmaier's research, conducted with Associate Professor of Pediatrics Todd Golub and with colleagues from the Broad Institute and from the Whitehead Institute for Biomedical Research, was published in the March issue of Nature Genetics.
Both Stegmaier and Golub said it's far too early to say whether any of the chemicals may result in a more effective treatment for AML, but Stegmaier is optimistic that the process could prove useful in the search for drug candidates for this and other diseases.
"There are many questions you can apply this screening model to, which was our hope," Stegmaier said.
Golub said the approach provides a new way to identify molecules that, even if they don't develop into treatments, can help scientists understand biological processes.
"Our chemist colleagues have taught us that small organic compounds serve as powerful tools to dissect biology," Golub said. "The GE-HTS approach represents a new strategy to find such molecules. Turning such molecules into drugs remains a nontrivial task, but if nothing else, GE-HTS-discovered compounds will be tremendously useful for the exploration of complex biological systems."