Disregard the organ it inhabits // target the mutation that fuels it // watch for signs it’s rebounding with another mutation // aim for that new target.
When the Drug Fits
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Christoph Niemann
Even seasoned cancer researchers, not usually given to hype, found a case study that appeared in the April 2008 issue of the Journal of Clinical Oncology miraculous. The patient, a 79-year-old woman, had bleeding tumors in her rectum and vagina, metastases of a very rare form of melanoma that affects mucous linings. A few days after she started taking the drug Gleevec, the bleeding stopped, and after four weeks a CT scan showed the tumors melting away. Nine months later, the patient’s condition was stable, and she was still taking her once-a-day dose of Gleevec.
The miracle, of sorts, was that Gleevec, one of the first targeted therapies (so called because they home in on one vulnerable, cancer-promoting mutation in a tumor cell), was never designed to treat melanoma. It was approved in 2001 to target a completely different kind of cancer (chronic myeloid leukemia) in a completely different organ (blood) because it blocks BCR-ABL, one of a class of proteins known as tyrosine kinases, which activate the molecular pathways that relay growth signals, allowing a cancer to flourish. It later turned out that Gleevec (imatinib mesylate) was also effective against c-KIT, another tyrosine kinase and the culprit in most gastrointestinal stromal tumors; the drug has since become the front-line therapy against that rare and previously deadly disease. The discovery that Gleevec can target c-KIT as well as BCR-ABL inspired researchers to try it on other cancers harboring a c-KIT mutation, including this woman’s melanoma.
This progress involving targeted therapies has implications for how cancers are diagnosed and treated and how clinical trials are designed. It adds weight to the idea that, for treatment purposes, tumors often need to be classified not by where in the body they occur but by the genetic mutation that causes them to grow and spread. Although gastrointestinal cancers and melanomas, for example, appear to be quite different, they seem to have much more in common than two kinds of breast cancer.
“The result reported in the Journal of Clinical Oncology sends a crucial message,” says David Fisher, chief of dermatology at Massachusetts General Hospital, who was involved in the melanoma study while at the Dana-Farber Cancer Institute in Boston. “If we know the underlying mutation and we have the right drug to target that mutation, we can treat even widely metastasized cancers for which we’ve had no effective therapy.”
Still, despite the dramatic effects of targeted therapies, they can accomplish only so much; when a drug blocks one pathway a cancer uses, it may take a detour and careen down a cellular bypass, making it resistant to the drug. All too often this means that a patient who experiences a seemingly miraculous recovery may succumb to a recurring cancer. That’s leading to a second generation of therapies designed to overcome tumors’ resistance to first-generation approaches, and drugs of both types now account for almost half of cancer-drug development. Making the best use of these new treatments may require oncologists to proceed much as physicians do when treating infectious diseases: by diagnosing the particular pathogen, in this case a mutation, before prescribing a therapy.
A wide array of changes conspire to let cells escape normal checks and balances on growth and behavior. Some mutations silence genes that typically would shut down undisciplined growth. Others cripple the mechanisms that repair DNA damaged during cancer’s rapid, reckless cell division or that, for cells beyond redemption, force them into apoptosis, a programmed suicide. And still others entice malignant cells to metastasize to far-flung organs. Cancer needs all these mutations to develop and flourish, and as it becomes more advanced, it accumulates more and more of them.
Given how many mutations it takes to render cancer cells malicious, it’s remarkable that most targeted therapies succeed by zeroing in on just one of them. This works because many cancers appear to become overdependent on a single cancer-causing gene, called an oncogene, that drives the runaway growth. This dependence gives them an Achilles’ heel, because blocking just this one oncogene with a targeted therapy makes the cancer cell screech to a halt, wither and die. Researchers often speak of this dependence as oncogene addiction, and they refer to the dramatic effect of targeted therapies as oncogenic shock, says Daniel Haber, director of the MGH Cancer Center.
Many addictive oncogenes belong to a large class that produces tyrosine kinases, which Jonathan Fletcher, a pathologist at Brigham and Women’s Hospital in Boston, describes as protein master switches. “They normally stay in the off position until they receive a message that the cell needs to divide,” Fletcher says. “Then they switch on and activate one growth pathway after another, like falling dominoes.”
In cancer, mutations essentially alter the shape of the switch, so it stays in the on position, flashing loud and incessant growth signals to downstream pathways. In targeted therapies, drug molecules latch onto the master switch and turn it off, preventing the kinase from transmitting its signal.
