FOCUS - June 24, 2005 - RESEARCH BRIEFS

Novel immune-boosting therapy with a hematopoietic growth factor may reduce symptoms and improve the quality of life for Crohn’s disease patients, according to a team of researchers from HMS, Massachusetts General Hospital, Washington University School of Medicine, and other institutions. Findings from their recent clinical trial appear in the May 26 New England Journal of Medicine.

Crohn’s disease, a chronic inflammatory disorder of the gastrointestinal tract, is currently treated with immunosuppressive agents to reduce symptoms only—there is no known cure. But new understanding of the pathophysiology of the disease, specifically that the cause may be due to a defect in the intestinal innate immune system, led researchers to hypothesize that a failure in the defensive barrier of phagocytic cells in the intestines may result in microbe exposure and thus an enhanced inflammatory response.

Lead author Joshua Korzenik, the co-director of the Crohn’s and Colitis Center at MGH, said the inflammation is secondary to an earlier problem—the defect in the body’s immune system. “If normal intestinal bacteria are not controlled by the innate immune system, a compensatory secondary inflammation could produce the symptoms of Crohn’s,” Korzenik said. The scientists based their research on the hypothesis that an immune enhancer could aid Crohn’s patients.

A total of 124 eligible patients with moderate to severe cases of Crohn’s received a daily 6 microgram dose of sagramostim, a recombinant human form of granulocyte-macrophage colony-stimulating factor (GM-CSF), in the randomized, placebo-controlled clinical trial, which took place at 28 centers across the United States. Of the 94 individuals who completed the experiment, the 57 GM-CSF–treated patients had higher rates of both response and remission than the 37 individuals in the placebo group. There were no significant differences in the overall occurrence of adverse events between treatment groups.

The experiment was supported by a grant from Berlex, Inc., and the researchers say larger studies are under way. “We’re encouraged that these results support this new understanding of Crohn’s and hope they will lead to a new treatment option for the disease,” Korzenik said.

—Rachel Patzer

Bench Science Advances Against Cancer

Several new areas of experimental cancer therapy are quickly advancing as researchers fine-tune their molecular attacks on tumors, said HMS researchers who spoke at a May 13 media seminar titled “The Future of Cancer Research,” held at the Whitehead Institute.

Twenty years of painstaking work by hundreds of scientists is now blossoming into a fruitful area of drugs targeted at the overabundance of kinases on the surface of cancer cells, which enable them to grow and divide.

Last year, two teams of HMS researchers independently discovered why one of the new drugs, gefitinib (Iressa), worked as well as it did in the small fraction of people whose small-cell lung cancers responded to the drug. A set of mutations in the target receptor kinase, epidermal growth factor receptor (EGFR), which cause the cancer, actually help the drug bind.

One of the groups, which includes Matthew Meyerson, HMS assistant professor of pathology at the Dana–
Farber Cancer Institute and a member of the Broad Institute, has now expanded its search for cancer-specific mutations in the tyrosine kinase protein family to 3,000 tumor samples representing 95 different cancers.

“The combination of genomic technology and targeted history provides a unique opportunity to understand the pathogenesis of cancer,” Meyerson told a room of reporters.

So far, the kinase inhibitors have not translated into as large a survival benefit as might be hoped. In some patients the lung cancers shrank by half in only six weeks, but then grew back completely resistant to the drug in about six months. The resistance comes from a second mutation that blocks the kinase’s drug-binding pocket.

“An effective drug to circumvent the resistance will have a big impact,” said Daniel Haber, HMS professor of medicine at Massachusetts General Hospital. Haber was part of a second team that identified the susceptible EGFR mutation, which blocks the normal apoptotic pathway that would normally cause the cell to die.

Such mutations allow doctors to identify patients who are most likely to respond to specific therapies, knowledge that reduces the size of clinical trials and speeds up drug testing, Haber said. As in HIV therapy, a cocktail of inhibitors targeted to different molecules is likely to be needed.

“Protein kinases represent a new paradigm in drug discovery,” said Juswinder Singh, associate director of structural informatics at Biogen Idec in Cambridge. Nearly one third of all pharmaceutical research and development is devoted to the 518-member family of known kinases, he said.

Emerging technologies that combine structural, chemical, and biological data and computational advances are ratcheting up the screening for small molecules that can bind to kin-ases and block their activity in cancer. “The new approach,” Singh said, “is to experimentally and computationally examine the effects of compounds against the whole protein kinase family, which is pivotal to biology.”

A different kind of cancer drug emerged from the lab of Alfred Goldberg, professor of cell biology at HMS, who 30 years ago discovered the proteasome, a large enzymatic machine in cells that selectively destroys misfolded proteins and critical regulatory proteins. He and several Harvard colleagues founded a small biotech company to generate molecules that block the proteasome’s ability to shred proteins, eventually leading to the drug Velcade, approved two years ago by the FDA for the treatment of multiple myeloma.

“Ironically, when we set out, cancer therapy was not our goal, but with time it became clear that in many cancers, oncogene products fail to get degraded or tumor suppressors get degraded too rapidly,” said Goldberg. Velcade is now in nearly 60 human trials against other cancers.

In contrast, Rakesh Jain set out to solve the paradox of clinical-trial results showing that chemotherapy works in combination with the new experimental anti-angiogenic agents, which are supposed to cut off the blood supply to the tumor. He proposed a new mechanism, which he and other researchers have confirmed. The anti-angiogenic agents transiently normalize the shoddy vessels hastily constructed by the tumor, and the temporarily improved vessels can deliver the chemotherapeutics more effectively before the tumor vasculature is pruned and becomes inefficient.

—Carol Cruzan Morton

top