ROW ON: Jacobs experimental combination therapy is so mild she can enjoy activities like paddling on Lake Lanier outside Atlanta
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The detective work required to combat cancer effectively starts with the malignant cell itself. A tumor is essentially an accumulation of mutations. It grows uncontrollably because its DNA, laboring under the weight of layer upon layer of genetic errors, has become unstable and unable to repair itself. By studying those mutations, scientists can learn quite a bit about how a particular cancer cell became malignant and the molecular pathways it uses to get the nutrients it needs to fuel growth. One or several of those mutations may turn out to be the tumor's Achilles' heel — a weakness that makes it vulnerable to a particular drug.
At the meeting in New Orleans, two groups of scientists, one based at Massachusetts General Hospital (MGH) and another at the Dana-Farber Cancer Institute, reported on their search for such a weakness among a small group of lung-cancer patients taking gefitinib (trade name: Iressa), a recently approved drug that blocks a key protein known as the epidermal growth factor. Cancer cells need epidermal growth factor to continue dividing; design a drug that blocks its action, and you can slow or even prevent further growth.
In the MGH trial, doctors studied 16 cancer patients who were treated with Iressa. Nine saw their tumors shrink, but the drug had little effect on the rest. It turns out that eight of the nine patients who benefited from gefitinib had mutations in the receptor that binds to the cancer's epidermal growth factor; none of the patients who didn't respond had the mutations. Growth factors tend to fit into receptors on a cell's surface like keys into locks. Somehow, the changes in the eight patients made their receptor locks a better fit for the gefitinib key.
In the Dana-Farber study, researchers looked at a larger number of patients in the U.S. and Japan and found a similar pattern with a different set of mutations in the same receptor. "Knowing that those drugs will work brings us closer to being able to screen patients and target the right drugs to them," says Dr. Thomas Lynch, who led the MGH study. His group is analyzing still more lung-cancer patients, and if the results hold up, doctors may soon be able to identify these super-responding patients as soon as their cancers are diagnosed. That will allow physicians to bypass chemotherapy and start these patients on gefitinib as their first line of treatment.
Tracking Changes
Cancer cells are not static creatures. As a tumor develops, it begins to change genetically and physically, and scientists are trying to identify those changes through the various compounds a cancer cell secretes as it ages. As they are released in the blood or urine, those compounds offer doctors a window onto the disease, allowing them to see what the cancer cells are doing without having to biopsy the tumor. "A tumor that was removed three years ago and has spread is probably not the same tumor anymore," notes Howard McLeod, a professor of oncology at Washington University in St. Louis, Mo. "For a tumor to have survived a first-line therapy, something changed to give it an advantage. For it to survive second-line therapy, something else changed. And for it to survive long enough to spread to other sites, then something more is different."
The better that researchers know a cancer, the better their chances of defeating it. Those odds also improve if doctors have more than one way to fight it. As they fill in the details — at the molecular level — of the world in which tumors thrive, doctors are becoming convinced that a one-drug-one-cancer approach is not sufficient. Just as AIDS physicians currently use a multi-drug approach to attack HIV at different stages of its life cycle, so too are cancer doctors beginning to surround tumor cells with combinations of agents that can weaken a growing cancer by chipping away at its life-support systems.
Already it is clear that the nature of those support systems is more important than where in the body the cancer originated. "The source of the cancer becomes less of an issue over time than trying to understand the signaling pathways the cell is using," says Dr. James Abbruzzese of M.D. Anderson Cancer Center. In coming years, doctors will think not of breast cancers and colon cancers but rather of growth-factor cancers and signaling cancers.