The Sol Goldman Pancreatic Cancer Research Center

What's New 2001

Unraveling the genetic changes in pancreatoblastomas
November 6, 2001

While scientists have made great strides in advancing our understanding of pancreatic ductal adenocarcinoma, little is known about rarer tumors that arise in the pancreas. In this month's issue of the American Journal of Pathology, S. Abraham and colleagues from Johns Hopkins report a detailed molecular genetic analysis of pancreatoblastomas. Pancreatoblastoma is a rare pancreatic tumor with a distinctive microscopic appearance that generally affects infants and young children (see the FAQ section of this Web site for more information on pancreatoblastomas and other rarer variants of pancreas cancer). Dr. Abraham analyzed a series of nine pancreatoblastomas for genetic alterations (changes in the DNA sequence of the tumors). She found three interesting things. First, pancreatoblastomas are genetically very different from the more common ductal adenocarcinomas of the pancreas. Most ductal adenocarcinomas harbor mutations in the k-ras, p53 and DPC4 genes, while pancreatoblastomas do not. Instead, pancreatoblastomas show alterations (mutations) in the beta-catenin/APC genes. 2) Dr. Abraham also showed that chromosome 11p is frequently altered in pancreatoblastomas. Chromosome 11p is frequently altered in hepatoblastomas (a rare pediatric tumor in the liver), suggesting that pancreatoblastomas are more closely related to hepatoblastomas than they are to pancreatic ductal adenocarcinomas. 3) Finally, one of the patients included in Dr. Abraham's series of pancreatoblastomas had the clinical syndrome called "familial adenomatous polyposis" or "FAP". Patients with familial adenomatous polyposis develop numerous polyps in their colon at an early age and Dr. Abraham demonstrates that they can also develop pancreatoblastomas.

Dr. Abraham's study is an important advance in our understanding of some of the rarer variants of pancreas cancer. Dr. Abraham's paper is available on-line at: http://ajp.amj pathol.org/cgi/content/full/159/5/1619



Physical Activity, Obesity, Height, and the Risk of Pancreatic Cancer
August 30, 2001

In this week's issue of the Journal of American Medical Association (JAMA), Drs. Michaud, Giovannucci, Willett, Colditz, Stampfer, and Fuchs from the Harvard School of Public Health and the National Cancer Institute report a large study of pancreatic cancer risk. They used two large groups of patients - the Health Professions Follow-up Study and the Nurses Health Study to determine the risk factors of pancreatic cancer. A total of 46,648 men and 117,041 women were free prior cancer at baseline were followed for 10-20 years. Remarkably, the authors found that decreased physical activity, obesity, and being tall increased the risk of pancreatic cancer. The effect of increased physical activity on decreasing the risk of pancreatic cancer was the greatest among those who are overweight. The association between obesity and physical activity and the risk of pancreatic cancer was explained, biologically, by the association of abnormal glucose (sugar) tolerance and pancreatic cancer.

While additional studies are needed, this large epidemiologic study certainly suggests that increased physical activity and weight reduction are reasonable measures that may, in addition to reducing one's risk of heart disease, reduce the risk of pancreatic cancer.

Reference:
JAMA 286(8):921-929, 2001

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Markers of Cancer Invasion
July 9, 2001

There is a great effort underway to identify new ways to identify cancers that otherwise would remain undetected for too long. A major approach is to identify tumor-specific markers and tissue-specific markers. For example, useful markers could be proteins found reproducibly to be produced by cancer cells in both tissue culture (cancer cells grown artificially outside the body) and in patient samples. But there is another potential type of marker, one that is produced by the invasive tumor or the body's reaction to it. Such markers would not be normally found in tissue culture and might not be present in normal tissues at a high level. These are the invasion-specific markers.

Dr. Ryu and colleagues in Dr. Kern's laboratory for pancreatic cancer research at Johns Hopkins searched for such genes. Dozens of invasion-specific markers were identified in invasive pancreatic cancers obtained from patient samples. Many of these were new markers not previously considered as cancer markers, and many of the genes are expressed not by the tumor cells but instead by the patient's response to the tumors. Some of these markers are known to be secreted and to be detectable in simple blood samples. A strong effort is underway to examine these candidates and develop markers for use in reliable assays for cancer that can be done on serum, to aid medical imaging, and to serve as targets for the development of invasion-specific anticancer therapy. The first such candidate marker was the subject of a recent paper by Argani and colleagues (See What's New, June 2001)

Reference:
Ryu, B., Jones, J., Hollingsworth, M. A., Hruban, R. H., and Kern, S. E. Invasion-specific genes in malignancy: Serial analysis of gene expression comparisons of primary and passaged cancers, Cancer Res. 61: 1833-1838, 2001. (abstract)

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Activin Receptors — A New Anticancer Signal in Human Tumors
June 25, 2001

The major problem with human tumors is a social one. Tumor cells do not obey the signals from their surrounding cells that should restrain their growth. To date, very few of such signals have been defined, and this limits our ability to understand and counter this basic abnormality.

Because of the need to understand these signals, there has been a great effort to identify genes that are mutated and turned off in tumors. These are the tumor-suppressor genes. The inactivation of these genes allows tumors to escape from the normal growth controls that the surrounding cells and tissue are trying to place on them.

Activin is a protein secreted by normal cells. To exert its action, activin must bind receptors on a cell. The receptors propagate a signal to the cell, but it was not previously known that these signals were able to suppress tumor growth. Mutations within the activin receptor gene were found recently in some pancreatic cancers by Dr. Gloria Su and colleagues in Dr. Kern's laboratory for pancreatic cancer research at Johns Hopkins. In tumors that lack the mutations, someday it might be possible to administer activin as a therapeutic strategy. It might also be possible to mimic the effects of activin on tumor cells by a precise molecular targeting using specially designed new drugs that directly activate the signal pathway without the need for intact receptors. This is a new idea that was previously unknown, but now can be explored. It is our hope that one can design a rational therapy that would specifically attack the most vulnerable components of pancreatic cancer.

Reference:
Su, G. H., Bansal, R., Montgomery, E., Yeo, C. J., Hruban, R. H., and Kern, S. E. ACVR1B (ALK4) gene mutations in pancreatic carcinoma, Proc Natl Acad Sci USA. 98: 3254-3257, 2001.

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Hopkins' Scientists use Molecular Tool to Discover New Markers of Pancreatic Cancer
June 7, 2001

In the June 1st issue of Cancer Research (http: //cancerres.aacrjournals.org/cgi/content/full/61/11/4320), Dr. Argani and colleagues from Johns Hopkins described the discovery of a new marker of pancreatic cancer. This new marker called "prostate stem-cell antigen" (PSCA) was discovered by using a technique developed at Johns Hopkins called "serial analysis of gene expression". Since the original description of SAGE, a group of cooperating scientists from a number of institutions have created an online database of gene expression that includes SAGE data on a variety of tissues and cancers. The investigators at Hopkins used this database to compare the gene expression levels in pancreatic cancer tissues with those seen in non-cancerous pancreatic tissues. The goal was to identify genes that were selectively "turned-on" in the cancers. One of the genes the Hopkins found using this approach coded for a protein called "prostate stem-cell antigen." Prostate stem-cell antigen is a gene that was originally thought to be largely restricted to prostate cells. Dr. Argani and colleagues demonstrate that prostate stem-cell antigen (PSCA) is, in fact, highly overexpressed in approximately 60% of primary pancreatic cancers. It is not expressed in the normal pancreas.

These findings are exciting for several reasons. First, they demonstrate the power of new technologies such as SAGE to discover new tumor markers. Second, PSCA, because it is selectively overexpressed in pancreatic cancers, maybe a useful marker for pancreatic cancer. Third, other groups have shown that PSCA can be an immune target and therefore PSCA is being explored as a target for the immune treatment of cancers. The demonstration of PSCA expression in pancreatic cancer suggests a new avenue for treating pancreatic cancers. That is, immunotherapy directed at cells expressing PSCA.

On an important side note, this work was supported, in large part, by generous donations from the friends and family of Michael Rolfe demonstrating the power of private giving to advance pancreatic cancer research.

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Familial Pancreatic Cancer
March 23, 2001

For years, isolated reports in the medical literature have suggested that pancreatic cancer runs in some families. For example, it has been reported that former President Jimmy Carter lost his father, brother and two sisters from pancreatic cancer.

In the current issue of Clinical Cancer Research (http://clincancerres.aacrjournals.org/cgi/content/full/7/3/738), A. Tersmette and colleagues from Johns Hopkins report that first-degree relatives (brothers and sisters, parents and children) of patients with "familial pancreatic cancer" have a significantly increased risk of developing pancreatic cancer. Tersmette and colleagues followed 341 families enrolled in the National Familial Pancreas Tumor Registry (NFPTR) and found that the first-degree relatives of familial pancreatic patients had an 18-fold increased risk of developing pancreatic cancer when compared to the general population (the "SEER" database). In this study, familial pancreatic cancer was defined as at least a pair of first-degree relatives with pancreatic cancer in a family. Remarkably, if there were three or more family members with pancreatic cancer when the family enrolled in the NFPTR, then the risk of other family members developing pancreatic cancer jumped to 57-fold greater than the general population.

This study firmly establishes that "Familial Pancreatic Cancer" is a real entity and it provides a quantitative measure of the risk of pancreatic cancer in these families. Importantly, studies such as this will form the basis for identifying individuals at-risk for developing pancreatic cancer who might benefit from new screening tests as they are developed.

If you have a strong family history of pancreatic cancer and would like to join the research studies currently underway at Hopkins, please consider joining the NFPTR. If you would like to join, please contact the Coordinator of the NFPTR, Kieran Brune (kbrune@jhmi.edu).

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New Vaccine to Treat Pancreatic Cancer
February 9, 2001

In the January issue of The Journal of Clinical Oncology (volume 19; 2001: pages 145-156), Dr. Elizabeth Jaffee and colleagues at Johns Hopkins report the result of a phase I clinical trial of a novel vaccine treatment for patients with a pancreatic cancer. The vaccine was produced by genetically altering pancreatic cancer cells growing in culture so that the cells would produce large quantities of an immune activating factor called "Granulocytic-macrophage colony-stimulating factor" (or GM-CSF for short). Dr. Jaffee treated 14 patients with this vaccine in a phase I dose escalation trial. The patients underwent surgery at Hopkins after which they received various doses of the vaccine. No dose-limiting toxicities were encountered. Instead, Dr. Jaffee was able to demonstrate that the vaccine induced an anti-tumor immune response in three patients who received the highest dose of the vaccine (>10x107 vaccine cells). Remarkable, these three patients remained alive and free of disease more than 25 months after diagnosis. Based on these results, Dr. Jaffee and her team will be conducting phase II trials of the GM-CSF vaccine. These trials are scheduled to begin in the late spring - early summer.*

*In order to evaluate the effectiveness of the vaccine, a 60 patient study is planned to begin in May, 2001. As much as we would like to offer the vaccine to everyone, eligibility criteria had to be established for this study. Patients with adenocarcinoma of the pancreas who have surgery Johns Hopkins Hospital to remove their pancreas cancer and who have no clinical evidence of spread of the cancer outside the pancreas will be eligible for this study. Patients with bile duct cancer or neuroendocrine tumors or islet cell cancer are not eligible. Please contact Dr. Elizabeth Jaffee or Barbara Biedrzycki, R.N. (biedrba@jhmi.edu) for more information on eligibility criteria.

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