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Enzyme May Help Pancreatic Cancer Hide February, 2008





Cancer cells in the lymph nodes of patients with pancreatic cancer appear to produce enough of a particular enzyme to thwart the body's immune system, according to scientists at Thomas Jefferson University, who say the discovery could help lead to improved treatment of the aggressive, fatal disease.

The enzyme, indoleamine 2'3-dioxygenase, or IDO, is the same one researchers believe prevents a woman's body from rejecting a fetus. Too much of the protein may keep the body's immune system from fighting the spread of pancreatic cancer in patients with the disease, according to Jonathan Brody, assistant professor of surgery at the university's Jefferson Medical College.

The findings, which bolster previous research, ultimately could mean better detection of pancreatic cancer's spread to lymph nodes and, possibly, an agent that might be used with chemotherapy drugs or other therapies to help fight the disease. An IDO inhibitor might help reduce metastatic cancer and make a patient a candidate for surgery, he said.

A pancreatic cancer patient's prognosis can depend on whether the disease has spread to lymph nodes; for many, discovery of the disease happens too late for effective treatment.

The Pancreatic Cancer Action Network estimates that 37,000 Americans were diagnosed with the disease in 2007 and that 33,370 died from it. Only 5% of pancreatic cancer patients survive beyond five years, said the organization, which promotes research of the disease.

Pancreatic cancer cells in lymph nodes produce enough IDO to bar the immune system's T-cells and attract cells that suppress the immune system's response to the tumor, the Jefferson researchers found. Metastatic cancer cells thus can survive in lymph nodes by avoiding the body's immune system, Brody said.

"This is a preliminary, solid study that we've done on pancreatic cancer," Brody said. Because there is so little hope for most pancreatic cancer patients, he said, "any sort of minor breakthrough like this is big news."

Liz Thompson, director of research and scientific affairs at PanCan, said, "We're looking at this with a great deal of interest." She said no method for early detection of pancreatic cancer currently exists.

"Right now we have very, very little that we can offer metastatic (pancreatic cancer) patients," she said. An IDO inhibitor used in conjunction with chemotherapy drugs or with a vaccine might help stop the disease, she said.

Previous preclinical research by other scientists also suggests IDO plays a role in keeping the immune system from attacking cells of various types of cancer.

Patients are being recruited for an early clinical trial of an IDO inhibitor - 1-methyl-D-tryptophan, or 1MT - to be conducted by Ames, Iowa, biopharmaceutical company NewLink Genetics and two universities, in conjunction with the National Cancer Institute, according to a National Institutes of Health online database. For their part, the Jefferson scientists wanted to explore whether pancreatic cancer cells that have spread to the lymph nodes expressed IDO to avoid being detected. They compared IDO in 14 lymph nodes where pancreatic cancer cells had spread with that in the primary tumors in the same patients.

In every instance, there was greater IDO protein expression in the cancerous lymph nodes. Meanwhile, in three cases of lymph nodes that were free of pancreatic cancers, there was little of the protein.

Brody said he and colleagues at Jefferson, including surgery department Chairman Dr. Charles Yeo, a leading pancreatic cancer surgeon, aim to collaborate with scientists researching IDO and cancer at another institution with the goal of developing a therapeutic inhibitor.

The team reported its findings at the recent meeting of the Southern Surgical Association, and the results have been accepted for publication in the Journal of the American College of Surgeons.

William Malachowski, associate professor of chemistry at Bryn Mawr College near Philadelphia, is part of a research group working to try to develop an IDO inhibitor.

"What several groups are working on, and including our group, is trying to develop a drug which would block this IDO," Malachowski said.

No such drug is on the market now, according to Malachowski, who also does work with Jefferson researchers but was not involved in Brody's study.

"The whole idea that this could be a cancer therapy is in its infancy," Malachowski said.

Malachowski works under an NIH grant with two scientists from Lankenau Institute for Medical Research near Philadelphia, George Prendergast and Alexander Muller, whose earlier research showed that IDO appears to allow breast cancer cells to escape immune response. He also serves as a consultant for NewLink Genetics, although he is not involved in the company's work on 1MT, the inhibitor now the subject of an early clinical trial.

Two primary pancreatic cancer drugs now on the market are Eli Lilly & Co. (LLY) chemotherapy drug Gemzar, or gemcitabine, and OSI Pharmaceuticals Inc. (OSIP) and Genentech Inc. (DNA) therapy Tarceva, according to Thompson. An older chemotherapy drug, 5FU, or fluorouracil, also is used to treat pancreatic cancer, she said.

Various efforts to develop new pancreatic cancer drugs have faltered, as trials showed that therapies failed to adequately help patients.

Among other promising research, Thompson cited work by scientists looking into endoscopic ultrasound imaging in high-risk patients aimed at finding pancreatic tumors when they are small. A trial is underway at four sites around the country, she said. Researchers also are looking at biomarkers in the blood that might allow doctors to catch the cancer at an early stage, and developing a potential vaccine, now in clinical trial, to halt the disease.

"No one believes that they have the one single answer for early detection or treatment of this disease," she said.

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