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- 19 December 2013 12:36 pm , Vol. 342 , #6165
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New Drug Shows Promise for Advanced Lymphoma
3 April 2012 2:45 pm
CHICAGO—The immune system cancer known as lymphoma can often be cured, but some types remain stubbornly resistant to treatment. Now researchers have found a drug that appears to help vanquish these lymphomas by targeting their abnormal cell wiring. Tumors shrank in four of 10 advanced lymphoma patients treated with the drug, and one is still in remission more than a year later.
Diffuse large B-cell lymphoma, which involves immune cells called B cells, is one of the more common and dangerous lymphomas. Each year about 23,000 people in the United States are diagnosed with it, and some 10,000 die annually. Over the past decade, cancer biologist Louis Staudt's team at the National Cancer Institute in Bethesda, Maryland, has analyzed patterns of gene activity within the malignant immune cells to break this cancer into subtypes, including one, activated B-cell-like (ABC) diffuse large B-cell lymphoma, that kills 60% of patients within 3 years. By dissecting the roles of different genes and proteins in the lymphoma cells, Staudt and colleagues have uncovered what appears to go wrong in this cancer: Genetic mutations cause B-cell receptors, proteins on the B cell's surface that normally recognize infections, to send signals into the cell that block a self-destruction process that normally helps rid the body of abnormal cells. In lab studies, the lymphoma cells died when treated with an experimental drug called ibrutinib that overrides this anti-suicide signal. The drug blocks a protein called Bruton's tyrosine kinase (BTK) that's part of the B-cell-receptor signaling pathway.
Now in a pilot clinical trial, Staudt's team has found that ibrutinib can help some patients with the ABC lymphoma subtype who had failed other treatments and were expected to die within months. Of 10 patients who took an ibrutinib pill daily, tumors shrank or disappeared in four. While two relapsed within a few months, one is still in remission after 16 months. The fourth patient's tumor stabilized enough that he could have all his B cells wiped out with a chemotherapy drug and replaced with new, noncancerous ones by a bone marrow transplant. Several patients in a larger, ongoing trial have also responded to the drug, which is being developed by Pharmacyclics Inc. in Sunnyvale, California, and Janssen Research and Development, LLC, in Horsham, Pennsylvania. (Pharmacyclics is sponsoring the trial.)
Surprisingly, Staudt says, only two of the responding patients in the pilot trial had the expected mutations in the B-cell receptor. That suggests to him that either there are more mutations to be discovered, or else the pathway is overactive for some other reason. For now, what matters "is that there's a new pathway for which there is a targeted therapy in which people are showing remission in a very aggressive lymphoma," says Staudt, who reported on the pilot study here Sunday at the annual meeting of the American Association for Cancer Research. The next step, he says, is to test the drug in combination with conventional chemotherapy.
Oncologist Jonathan Licht of Northwestern University Feinberg School of Medicine in Chicago, Illinois, says targeting the B-cell-receptor pathway could be important not just for lymphoma but for several other cancers for which ibrutinib is also being tested in trials. But one challenge will be to show that the inhibitors are actually blocking the BTK protein and not working through some other mechanism. "It's very promising," he says, "but it remains to be shown whether these drugs are hitting their target."