In 2003, geneticist and oncologist Daniel Haber was reading an article in the Boston Globe when he had an idea. The story described a woman with advanced lung cancer who came to Massachusetts General Hospital to be treated with an experimental drug known as Iressa. The drug had little or no effect on most cancer patients, but this woman “had an almost instantaneous response,” he recalls. “As of this day, five years later, she is still free of disease—we celebrate every year.”
The woman's experience reminded Haber of the successful treatment of a form of leukemia with the drug Gleevec (imatinib), which blocks a specific protein required for the leukemia cells to grow. Haber wondered if the same miraculous response might also have happened to the woman described in the newspaper article.
Haber had never worked on lung cancer before, but he was determined to follow up on his hunch. He and his colleagues obtained cells from nine patients whose lung cancers had responded well to Iressa (gefitinib). They then sequenced the gene in each of the patients for a protein known as epidermal growth factor receptor (EGFR), which promotes growth in normal cells and is blocked by Iressa. Eight of the nine patients had mutations in the gene. Haber's group also sequenced the genes of seven people who did not respond to the drug. None had the mutations.
Haber's discovery has contributed to a new way of looking at cancer. Cancers result from mutations in multiple genes that cause cells to grow out of control. But some cancers are “addicted” to particular mutations. “Even though a cancer cell may have hundreds of mutations, some cancers are wired in such a way that a particular mutation drives the cancer,” Haber said. “It is a crutch that the cancer relies on for survival. And when that crutch is removed, the cancerous cells die.”
Haber was in an ideal position to link lung cancers to genetic mutations. Since establishing his laboratory in 1991, he has focused on cancer genetics. In particular, he has a long-standing interest in Wilms' tumor, a cancer of the kidneys that occurs predominantly in children. Haber characterized a tumor suppressor gene known as WT1 that is mutated in 10 percent of patients with Wilms' tumor, and he recently discovered a gene on the X chromosome (WTX) that is mutated in as many as 30 percent of pediatric kidney cancers. He has studied other genes that are involved in genetic susceptibility to breast cancer, including BRCA1, BRCA2, and CHEK2.
By linking EGFR mutations to certain lung cancers, Haber has made it possible to identify patients who will react well to drugs like Iressa, Tarceva (erlotinib), and others of the class that block EGFR. However, practical difficulties remain. Even in patients who respond well to Iressa, cancer often recurs within a year or two. In some cases, new mutations in the EGFR gene prevent binding by the drug. To overcome this, Haber and other researchers have been experimenting with “irreversible” EGFR inhibitors that bind so tightly to the receptor that they permanently disable its function.
For patients with other types of cancer, mutations in genes other than EGFR have opened alternative pathways to targeted therapies. An effective way to tackle this problem—for many different types of cancer—is to model drug sensitivity in genetically characterized cancer cell lines, Haber said. For example, studies of gastric cancers have identified high-level amplification of a gene for the MET receptor in about 20 percent of cases. “These cancers appear to be very sensitive to MET inhibitors, whereas other gastric cancer cells without MET amplification are insensitive to the drug,” Haber said. “We are now trying to identify those patients who are susceptible to treatment with this inhibitor.”
Haber's group is now working on a collaboration to screen more than 1,000 cancerous cell lines, representing a broad spectrum of genetic heterogeneity across many cancer types, for specific drug-sensitivity patterns. The strategy is “incredibly useful to predict what fraction of cancers have genetic markers that can be applied clinically to guide clinical trials of molecular targeted agents,” he said.
Sometimes Haber marvels that a major component of his research is based on an insight derived from a newspaper article. “That was as close as I ever came to a true eureka moment, where you ask yourself, `What if?' and it turns out to be true. I hope I live to see that happen again.”