OHSU Cancer Institute Researchers Use Shortcut To Identify New Treatment Target For Leukemia
07/17/06 Portland, Ore.
Researchers take another leap forward in personalized cancer medicine through the development of a new, fast approach to analyzing molecules from cancer cells for cancer-causing mutations
Using a new, fast and relatively inexpensive approach to identify molecular abnormalities that cause normal human cells to turn into cancerous ones, researchers at the Oregon Health & Science University Cancer Institute have identified a new treatment target for acute myeloid leukemia (AML), and potentially other cancers.
"This approach makes it possible to quickly find molecular mutations that drive a patient's cancer so we can do something about it," said Brian Druker, M.D., JELD-WEN chair of leukemia research in the OHSU Cancer Institute and an investigator with the Howard Hughes Medical Institute. "It moves forward the personalized medicine model where cancer treatment is tailored for each patient based on the molecular mutations at the heart of his or her cancer."
In search of a more efficient screening strategy than DNA sequencing for spotting cancer-causing mutations in molecules, researchers devised a new application of mass spectrometry, an existing technology capable of capturing a chemical snapshot of the inner workings of a cell, in combination with other technologies. Within less than two months they found three activating mutations of the tyrosine kinase JAK3 in AML cells. Their study will be published in the July issue of Cancer Cell.
"DNA sequencing is very labor intensive, costly, time consuming, and the vast majority of mutations it identifies don't cause cancer," said Jeffrey Tyner, Ph.D, a senior author of the study and a postdoctorate fellow conducting research in Druker's lab.
DNA sequencing is an analysis of the roughly 30,000 genes found in a cell. It can be used to help pinpoint cancer-causing mutations in genes.
"It may have taken years to find these mutations with DNA sequencing alone," Tyner said. "As we streamline our process, we will be able to analyze cancer cells for mutations in a matter of just weeks."
In collaboration with Cell Signaling Technologies, researchers used mass spectrometry to study chemical reactions involving proteins set off within cells by activated tyrosine kinases. These reactions, known as phosphorylation, help regulate cell growth and cell survival by turning proteins on and off. Mutated tyrosine kinases can become stuck in the "on" position, producing large numbers of phosphorylated proteins, and bringing about cancer-causing malfunctions in the life cycles of cells.
"This strategy works because we are using the biochemistry of the cell to tell us where the abnormalities lie and we can then work backward to pinpoint the mutation," Tyner said. "So instead of screening through thousands of genes without a priori evidence, we can quickly narrow the field to a handful of genes based on this biochemical snapshot of the cell."
Mass spectrometry itself is not new. "What is new is the ability to use this machine to analyze and identify larger, more complex biological molecules such as proteins based on their structure," Tyner said.
Ninety tyrosine kinases help regulate human cells. It took about two weeks from the start of the experiment for researchers to narrow down to five the field of candidate tyrosine kinases responsible for the growth of a particular AML cell line. In just one more week, they had applied other technologies, including tyrosine kinase inhibitors, to narrow the field to one, JAK3.
During the next couple of weeks, researchers used these studies to guide DNA sequencing and quickly identify a mutation in JAK3 that caused it to be active or stuck in the "on" position. Further DNA studies of JAK3 led to the identification of two more mutations in patients with acute myeloid leukemia.
"What's really exciting about this finding is that an inhibitor of JAK3 already exists and is now being evaluated for other purposes in clinical trials," said Druker, a senior author of the study and scientific leader of the lab conducting the research. "More research needs to be done, but a plausible Gleevec-type treatment for JAK3 mutated AML already could be out there."
Druker's research of tyrosine kinsases in another type of blood cancer, chronic myeloid leukemia (CML), led to the development of Gleevec, the most successful targeted cancer therapy to date. Gleevec works by inhibiting the mutated tyrosine kinase at the root of CML. The overall survival of CML patients taking Gleevec at five years is 89 percent as compared with no more than 50 percent with prior therapies, and the risk of relapse continues to decrease the longer patients take the drug.
"Our new research validates the possibility of progressing very quickly from collecting cancer cells from a patient to identifying the kinase driving the cancer to selecting a therapy to stop the kinase," Druker said. "There are about a dozen known tyrosine kinase inhibitors like Gleevec available today that might very well help cancer patients with corresponding tyrosine kinase mutations."
AML is the most common leukemia among adults in the United States. "Our hope is to apply this approach across many kinds of cancer," Druker said, "so one day soon we can have a Gleevec for every cancer."