As Cancer Drugs Become Stronger, So Do Side Effects Research
New York Times Syndicate
During the past couple of decades, cancer researchers have sought to understand how the disease corrupts cells and then proliferates through the body.
As they have better understood cancer's molecular underpinnings, scientists have developed more powerful drugs to target the mechanisms by which cancer thrives.
But along with more powerful drugs have come significant side effects.
So now scientists are, in turn, trying to understand the precise ways in which some of the most common cancer drugs cause side effects, in hopes of improving the existing cancer drug or using additional therapies to target the side effect.
These efforts are beginning to show some success. Houston researchers have found precisely how a kidney cancer drug, sunitinib, damages the blood vessels leading to the heart.
"In an era of molecular and cell-specific drug development against human cancer, it is fundamental to uncover the mechanisms of off-target side-effects," said Dr. Wadih Arap, who along with his wife, Renata Pasqualini, was among the local researchers who made the discovery.
The husband-and-wife team, researchers at the University of Texas M.D. Anderson, recently were recruited to take leadership positions at The University of New Mexico Cancer Center.
'The whole picture'
The new research highlights several important points about cancer: The disease is incredibly complex, treatments are likely to become more complex as a result, and the range of scientific talent needed to understand cancer is broad indeed.
Solving the mystery of why sunitinib was causing heart problems required not only cancer scientists but heart specialists as well as cell biologists like Nathan Bryan, at the University of Texas Health Science Center at Houston.
"This kind of collaboration is one of the great things about being at the Texas Medical Center," Bryan said. "To understand complex problems like, this we need to see the whole picture."
The authors of the new study, published recently in Science Translational Medicine, hail from M.D. Anderson, UT-Houston and Baylor College of Medicine.
Most of the basic research was done at M.D. Anderson, where it was led by cancer scientist and study co-author Aarif Khakoo, who now works for Amgen, a drug company.
Khakoo said he and his colleagues wanted to understand the biological reasons for unexpected cancer drug toxicities, and they zeroed in on a class of drugs called kinase inhibitors.
Scientists previously had identified some kinases - a type of biological molecule involved in cell growth - as targets for cancer drugs. This is because certain kinds of kinases appear to enter a state of hyperactivity when cells go bad and become cancerous.
This understanding led drug companies to develop drugs to inhibit the actions of certain kinases.
Later, scientists were surprised to find that some of these kinase inhibitors, as well as other types of cancer drugs, caused human patients to develop heart problems.
"We thought that was interesting, and we really wanted to understand it," Khakoo said.
Through a series of experiments in mice, the researchers found that sunitinib destroys small protective cells, called pericytes, that wrap around blood vessels in the heart. Mice given sunitinib no longer had any pericytes coating their blood vessels.
The 'wow' moment
In essence, then, the scientists found that some of the same biological processes involved in the early development of cancer also are involved in the protection of blood vessels.
"For us, that was the 'wow' moment," Khakoo said.
The findings underscore the idea that many cancer researchers hold - that the curing of cancer will not come soon nor easily.
As part of a perspective published in the same journal, two Harvard Medical School cancer scientists, Javid Moslehi and Susan Cheng, argue that insights like this new work indicate researchers are still looking at the tip of the iceberg when it comes to understanding and comprehensively treating cancer.
In other words, there's a lot more scientists need to know about cancer than they already know about the complex disease.
That's an assessment with which Khakoo agrees.
"And as we make more potent cancer drugs," he said, "we may see new toxicities that we will need to understand."
The good news is that with understanding comes the ability to adapt.
The Houston researchers found that by giving mice another drug that protects pericytes, thalidomide, they found that they could prevent heart damage while preserving the cancer-fighting ability of sunitinib.
After testing in humans, this kind of multi-drug therapy could soon help people suffering with cancer today.