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U-M CCC - Progress Newsletter Fall 2003 Online

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Pancreatic cancer genes identified in most comprehensive and accurate study to date

Further research may improve diagnosis and treatment for #4 cancer killer

Being diagnosed with pancreatic cancer is like receiving a death sentence -- one that, for many patients, is carried out within weeks or months of their cancer's discovery. Less than 20 percent of patients are diagnosed in time to qualify for the only known cure -- an arduous operation -- and only 3 percent of all patients live even five years.

But a team of researchers from the U-M Comprehensive Cancer Center hopes to overturn that death sentence, through studies that zero in on the genes and proteins that help pancreatic cancer grow and spread.

In a paper published in the May 15, 2003 issue of the journal Cancer Research and through work funded by a $2.36 million Michigan Life Sciences Corridor grant, as well as a patient care clinic launched earlier this year, the team aims to find new ways to improve diagnosis and treatment of the deadly disease.

In the paper, the team reported finding 158 genes specific to pancreatic cancer -- the most accurate list to date.

The U-M team was able to distinguish genes involved in cancer from those involved in a chronic inflammatory disease, pancreatitis, that's often mistaken for cancer. Both diseases produce similar scar tissue around the pear-shaped pancreas gland, which produces insulin, hormones and digestive juices. The team narrowed the list of genes down to 80 that were expressed three times more often in pancreatic cancer cells than in non-cancerous or pancreatitis cells.

The team believes its results will be more applicable to making specific diagnostic tests and effective treatments. The new paper even reports their success in identifying and detecting four of the proteins -- 14-3-3-sigma, S100P, S100A6, Beta-4 integrin -- that are encoded by the cancer-specific genes. The grant allows for continued protein cataloging and identification of the protein "biomarkers" that could be used in diagnostic tests or treatment planning.

"Pancreatic cancer is one of the swiftest and surest cancer killers, and not nearly enough has been learned about what, at the molecular level, makes it so deadly," says Craig Logsdon, Ph.D., lead author of the paper and principal investigator on the grant. "Others have made lists of genes that might be involved, but our study provides a much more accurate accounting, and reveals dozens of novel genes."

Logsdon, a professor of physiology at the U-M Medical School, co-leads the team with Diane Simeone, M.D., an associate professor in the U-M Department of Surgery's Gastrointes-tinal Surgery division. Simeone directs studies of the cancer in her basic research laboratory.

Late diagnosis, a lack of effective treatment options, rapid metastasis, and a dearth of research on how pancreatic cancer works combine to make the nation's 10th most common cancer into the fourth most deadly. More than 29,000 Americans are diagnosed with pancreatic cancer each year, most of them already too far advanced to be treated.

"We truly need a better understanding of pancreatic cancer, to help improve the terrible odds that these patients face because of late diagnosis and treatment resistance, and to spare pancreatitis patients unnecessary surgery because of misdiagnosis," says Simeone. "Protein biomarkers, which we hope will be easier to find now that we have our gene list, may help us find ways to make diagnosis more accurate, and to tailor treatment to individual patients."

More than 200 pancreatic cancer patients a year receive treatment at the U-M Cancer Center, taking part in clinical trials that combine surgery, radiation therapy and chemotherapy in an effort to improve the cancer's response to treatment. Simeone and her colleagues have established a new Multidisciplinary pancreatic cancer clinic to give patients access to a broad range of clinical and supportive care, and to help speed the clinical trials process.

She notes that statistics show patients do best at centers such as U-M that treat many cases each year, and that even patients who face no chance of survival often want to help research by enrolling in clinical trials or donating tissue.

U-M pancreatic cancer patients are now being added to a database that will track their treatment experience, and allow the research team to study their tumor tissue, blood and saliva for further clues to the cancer's molecular workings. Support from the Susan Nucian Fund for Pancreatic Cancer Research makes this database possible.

Logsdon and Simeone say their next targets will be genes that are expressed early in the development of cancer, and those that encode proteins found on the surfaces of cancer cells. This approach will speed the development of potential diagnostic tests, and of immunotherapies that target cancer cells while sparing normal tissue.

"We're focusing U-M's resources on pancreatic cancer, combining clinical and basic science in a way we believe will help accelerate the progress on this disease," says Logsdon. "This gene list is a very promising start, but there is still far to go."

The new Multidisciplinary Pancreatic Cancer Clinic is now open each Monday. Consultations with surgical oncology, medical oncology and radiation oncology specialists are available the same day for patients with suspicion of or the diagnosis of pancreatic cancer. In most instances, patients will be seen in the clinic the Monday following a referral. To schedule an appointment, call the clinic directly at (734) 647-8902 and ask to speak with the scheduling coordinator. More information about the clinic is also available on their website.

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U-M Scientists find protein that controls prostate cancer's spread

Cancer specialists know that it's not usually prostate cancer itself that kills -- it's the spread of the cancer from the prostate to the rest of the body. But relatively little is known about exactly what makes some men's cancers spread, or metastasize, while other tumors stay put.

Now, a study by scientists at the U-M Comprehensive Cancer Center reveals one crucial key to that deadly process. As reported in the June 18 issue of the Journal of the National Cancer Institute, the U-M team has found strong evidence that a protein called RKIP, for Raf kinase inhibitor protein, governs the ability of prostate cancer cells to leave their original location and enter nearby blood vessels -- which then act as superhighways to the rest of the body. The findings show that RKIP is vital to this process, called vascular invasion. Such invasion is the first in a cascade of events leading to metastasis. Tumors that produce a normal amount of RKIP appear unable to make the jump to the vascular system. But if a tumor cell lacks RKIP, metastasis can take place.

"The gene encoding RKIP appears to be a novel metastasis suppressor gene, involved in blocking the cell-signaling processes that allow cancer cells to enter the bloodstream," says senior author Evan Keller, D.V.M, Ph.D., an associate professor of Comparative Medicine and Pathology at the U-M Medical School. "If there is RKIP expression in a tumor, this first important step appears to be less likely."

The study may eventually lead to tests that could tell dangerous forms of cancer from those less likely to spread, since the presence of RKIP can be detected by a simple tissue-staining method. Or, it could lead to gene therapy to replace RKIP -- and prevent metastasis -- in those whose tumors don't produce it.

But Keller and his colleagues, including first author and U-M postdoctoral researcher Zheng Fu, Ph.D., note that it could be several years until RKIP-based tests or treatments will be available. Continued study of RKIP's role is needed, they say.

The paper documents three and a half years of work, using various techniques to thoroughly assess RKIP's function. The resulting evidence may be the first time a metastasis suppressor gene has been studied so thoroughly and the mechanism of its action determined so precisely. About 20 genes involved in the metastatic cascade have been found, but most have yet to be correlated with a specific action or function in the body.

Keller notes that vascular invasion -- the "first step" in metastasis apparently governed by RKIP -- is not the only action necessary for cancer to spread in a patient's body. "Many cancer cells that enter the bloodstream don't go on to form successful metastases," he says. But he predicts that the U-M team's discovery will help scientists and clinicians better understand the complex process by which some cancers kill. "These findings bring home the point that if you can stop even one gene in the cascade, you can slow the process down," he adds "Others have made lists of genes, but our study provides a much more accurate accounting, and reveals dozens of novel genes." Craig Logsdon, Ph.D.

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