Fighting Acute Lymphocytic Leukemia
Over the last four decades, the cure rate for acute lymphocytic leukemia has improved remarkably: it’s gone from 4 percent to 80 percent in the first world. Still, the disease claims about 10,000 young lives each year. Cincinnati Children’s researcher Jose Cancelas, MD, PhD, is working to close that gap, and he says that a specific protein is responsible for most cases that have a darker prognosis. "Most childhood acute lymphocytic leukemia can be cured, except for in kids that have this protein," he said. The protein is called p190 BCR-ABL, and Cancelas is working out a multiple-pronged attack on it.
Cancelas is not the first researcher to look at p190 BCR-ABL. In fact, Novartis and Bristol-Myers have developed drugs that block p190 BCR-ABL, increasing survival for patients with the protein from 10 to 30 percent. "But this is not good enough," said Cancelas. "The problem is that the protein is very big and complex, and these drugs only block part of it."
When drugs target a specific site, the protein can adapt to the new drug and work around it, much in the way that bacteria become resistant to antibiotics. "The cells responsible for the initiation of leukemia divide quickly, and mutations occur all the time," said Cancelas. "Cells with mutations that enable the protein to get around the drug survive, and pretty soon all of the remaining cells are resistant."
To prevent resistance, Cancelas works to block not only the p190 BCR-ABL protein, but also a cascade of other proteins that it activates to make the leukemia grow. This would be much harder for the leukemia cells to resist, since a single mutation couldn’t get around a variety of roadblocks at once. "If you target only one signalling pathway, it’s not useful because of mutations or other forms of resistance," said Cancelas, "if you target other parts you have the ability to eradicate the disease."
Already, Cancelas’s colleague Yi Zheng, PhD has developed a drug that blocks one of the proteins much farther along in that cascade. This protein is called RAC. "When you block RAC, you can see that you can block leukemia formation," said Cancelas. "We’ve seen that in vitro [test tubes] and in vivo [mice]. It worked very well."
But Cancelas and Zheng are still working to target proteins a bit farther up in the cascade—somewhere between P190 BCR-ABL and RAC--so that the drug will have fewer toxic effects. "RAC is found in every cell, and it plays a role in a variety of processes—not just leukemia," said Cancelas. "If we can target more specific proteins higher up in the cascade, we might be more specific and therefore less toxic."
Cancelas and his team are in a good position to develop more targeted drugs because they have genetically engineered mice to elucidate the pathway, and they have an efficient drug to knock out RAC, which will be of great help in revealing other aspects of the cascade. "We suspect a group of proteins that activate RAC," said Cancelas. "We are now trying to elucidate which ones are most important so we can target them too."
