The kinase race
Duplicating Gleevec's success story
By Richard Saltus
Guillermo Paez, PhD, prepares DNA from human tumor samples to be "read" in search of mutant genes.
Many times in military history, a sudden attack by a small, fast-moving force has broken an impasse and helped turn the tide against an entrenched foe. In such situations, timing is everything.
Dana-Farber researchers, sensing an opening in the cancer battle, are mounting a quick thrust to flush out suspected molecular cancer triggers in tumor cells. Drug companies can then select specific compounds that block these triggers, turning off the cells' stimulus to grow, but leaving normal cells unaffected.
The scientists are scanning the DNA from human tumor samples, sifting through their genetic blueprints for genes that produce abnormal growth-stimulating proteins known as tyrosine kinases. These mutant proteins behave like stuck "on" switches, causing unruly cell growth. The beauty of the plan, the investigators say, is that pharmaceutical companies have already developed hundreds of different drugs that inhibit tyrosine kinases, so they can quickly move these agents into clinical trials in humans. The approach could shave years off the customarily long delay between finding a vulnerable target in cancer cells and then testing new drugs to attack it.
Kinases are enzymes in cells that regulate their behavior, including when they should grow and when they should rest. Damaged kinases have been found in many types of cancer, where they spur the cells into runaway malignant growth. Many of those kinases belong to the group called tyrosine kinases. Of the 500 kinases in the human body, 94 of them are of the tyrosine type.
The new campaign was inspired by Dana-Farber research on tyrosine kinases in the 1980s and '90s that paved the way for the highly successful cancer drug Gleevec. It was among the first agents to take aim at specific mutant tyrosine kinases as a cancer therapy. Gleevec has stopped or shrunk tumors in many patients with chronic myeloid leukemia (CML) and gastrointestinal stromal tumor (GIST), a disease that had been virtually untreatable.
But these are two relatively rare cancers. Now the scientists want to open a wider front against more common forms. They have begun culling DNA from human tumors, hoping to process about 500 samples within a year in search of overactive tyrosine kinase proteins. They're hunting them by sequencing their blueprints — the DNA in the genes that produce the proteins.
As they discover new mutated kinases, the scientists will disseminate the findings so that pharmaceutical companies can match them with inhibitors already on the shelf. Development of these drugs has sped forward in recent years after it became evident that blocking kinase-stimulated cell growth was a promising new approach for combating cancer.
A computer representation of a kinase molecule shows its complex structure, which scientists study when designing drugs to block these enzymes.
"We want to repeat the Gleevec example over and over again," says DFCI's William Sellers, MD, who with Matthew Meyerson, MD, PhD, spearheads the collaboration among investigators at Dana-Farber and the Whitehead Institute/MIT Center for Genome Research. Based at the Massachusetts Institute of Technology, the latter is the largest facility of its kind for decoding DNA information from cells. It uses dozens of robot sequencers to read the genes' messages and massive computers to interpret their significance.
The investigators say the stars are aligned to press this search, named the Kinase Project. Todd Golub, MD, who is affiliated with both institutions, notes that Dana-Farber researchers had the foresight several years ago to begin freezing patient tumor samples and "waiting for the day they had technology in hand to make these kinds of discoveries."
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