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At some point in Karen Pihl’s life, one of her lung cells made a potentially fatal misstep. As the cell duplicated its DNA in preparation to divide, part of the gene for one protein became erroneously attached to part of the gene for another. The genetic malfunction bestowed the cell with the ability to grow out of control, ultimately creating lung cancer.

Today, Pihl is part of a clinical trial, being published in the New England Journal of Medicine, of an experimental lung cancer drug that specifically blocks the effects of that mutation. According to the findings, the drug, called crizotinib and developed by Pfizer, shrank tumors in half of patients whose cancers carried a similar genetic mistake. The drug suppressed tumor growth in another third.

While larger studies are still needed before the drug can be approved by the U.S. Food and Drug Administration, researchers hope it will provide a more effective and less toxic alternative for the approximately 2 to 7 percent of patients with non-small-cell lung cancer that carry this mutation. Traditional chemotherapies can affect both healthy and cancerous cells, leading to severe side effects. But targeted drugs such as this one act only on cancer cells, which typically means the drugs are much easier for patients to tolerate.

Pihl underwent chemotherapy and radiation therapy after her initial diagnosis in 2004, only to have her cancer return. Seeking a second opinion, Pihl went to Massachusetts General Hospital in Boston, where her doctor screened her cancer cells for specific genetic mutations that might render it susceptible to experimental drugs.

Three weeks later, Pihl received news that she was eligible for an ongoing clinical trial of the Pfizer compound. She began taking the experimental drug in March 2009 and has been on it ever since. “Each scan showed a decrease in the size of tumors, and the last scan showed scant remains or nothing,” she says. In contrast to the chemo and radiation, “the side effects of the drug have been so minimal for me,” she says.

Scientists have long known that cancer cells flourish thanks to an accumulation of genetic mutations that allow the cells to grow out of control. With advances in genomics technologies, including cheaper gene sequencing and microarrays designed to detect specific genetic sequences, the number of known genetic mutations linked to cancer is growing rapidly.

These studies have revealed that individual tumors carry a unique profile of genetic mutations, which in turn has led to an entirely new way to classify cancers. In addition to looking at the shape of cancer cells and other traits visible under a microscope, as is typically done today, scientists can use molecular tools to search for specific genetic variations.

These markers are increasingly being used to predict a patient’s prognosis and to select the drugs that will be most effective in tackling the particular molecular mistakes underlying their cancers. Pihl’s specific mutation creates what’s known as a fusion protein, when the genes for two proteins are mistakenly joined. First discovered in 2007 by Hiroyuki Mano, a scientist at the University of Tokyo, Pihl’s mutation tacked half a protein called EML4 onto a receptor known as ALK. The outcome is a permanently activated receptor “which continuously sends out proliferation signals that directly lead to cancer,” says Mano.

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Credit: New England Journal of Medicine 2010

Tagged: Biomedicine, cancer, drugs, tumor, lung cancer, targeted drugs

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