The Sol Goldman Pancreatic Cancer Research Center

What's New 2000

One Family Makes a Difference
December 15, 2000

The family and friends of Michael Rolfe have turned their terrible loss into something wonderful. With vision, dedication, and hard work, the Michael Rolfe Research Foundation has raised over $250,000 for pancreatic cancer research at Johns Hopkins. The general support of the Foundation has led to the creation of a new laboratory for pancreatic cancer research at Johns Hopkins. This laboratory will be headed by Dr. Gloria Su and will be dedicated to developing a much-needed mouse model of pancreatic cancer. At the same time, the Michael Rolfe Research Foundation has had the vision to establish an endowment at Johns Hopkins. The interest income from this endowment will be used to support the Early Detection Laboratory at Johns Hopkins. Just as there is a PSA test for prostate cancer, so to is this laboratory dedicated to developing a test for the early detection of pancreatic cancer.

On November 30, 2000, Judy Rolfe, Lisa Rolfe Burik, James Rolfe, and Hazel Herzog visited the laboratory at Johns Hopkins and presented the pancreatic cancer researchers with a check for $100,000. This check represents the income from the 1st Annual Michael Rolfe Research Foundation Gala that was held in Highland Park, Illinois in August. Photographs of their visit to Hopkins which included the dedication of a plaque in honor of Michael Rolfe can be seen below. Click here for details about Michael Rolfe and the Michael Rolfe Research Foundation.

The generous support of the Michael Rolfe Research Foundation exemplifies how private donations can honor loved ones and, at the same time, have a significant impact on the war against pancreatic cancer research.

Hazel Herzog, Dr. Mike Goggins, Dr. Gloria Su, Dr. Ralph Hruban, Judy Rolfe, Lisa Rolfe Burik, Jim Rolfe
Hazel Herzog, Dr. Mike Goggins, Dr. Gloria Su, Dr. Ralph Hruban, Judy Rolfe, Lisa Rolfe Burik, Jim Rolfe

Jim Rolfe, Judy Rolfe, Lisa Rolfe Burik
Jim Rolfe, Judy Rolfe, Lisa Rolfe Burik

Plaque of Michael Rolfe's support to Pancreatic Cancer

Lisa Rolfe Burik (at the scope), Ralph Hruban, Hazel Herzog
Lisa Rolfe Burik (at the scope), Ralph Hruban, Hazel Herzog

Jim Rolfe
Jim Rolfe

Dr. Christophe Rosty Lisa Rolfe Burik, Dr. Gloria Su and Dan Lin
Dr. Christophe Rosty (left) & Lisa Rolfe Burik, Dr. Gloria Su, Dan Lin (right)

Dr. Steven Leach Dr. Liz Jaffee
Dr. Steven Leach & Dr. Liz Jaffee

Dr. Mimi Canto Dr. Scott Kern
Dr. Mimi Canto & Dr. Scott Kern


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Hopkins' Scientist Isolate Genes from Tumor Vessels
August 22, 2000

In an exciting advance which may lead to new cancer therapies, Dr. St. Croix in Bert Vogelstein and Ken Kinzler's laboratory at Johns Hopkins reported their analysis of blood vessels from normal and cancerous colon tissues in this week's Science (August 18, 2000: 1197-1202). Using a powerful new technique developed at Hopkins, called serial analysis of gene expression (SAGE), Dr. St. Croix and colleagues were able to identify 46 genes which appear to be specifically elevated (or "turned on") in tumor-associated blood vessels.

The identification of these genes is exciting because such genes could potentially be targets for new drugs aimed at shrinking tumors by starving them of their blood supply. Alternatively, these genes which are selectively "turned on" in the tumor blood vessels could be used to specifically target therapies to the cancer. Importantly, most of the genes they identified were also "turned on" in a wide range of different tumor types, including pancreatic cancer, suggesting that the findings of Dr. St. Croix and colleagues could be translated to pancreatic cancers.

Dr. St. Croix's paper is available on the Web at http://www. sciencemag.org/cgi/content/full/289/5482/1197

Reference:
St Croix, B., Rago, C., Velculescu, V., Traverso, G., Romans, K.E., Montgomery, E., Lal, A., Riggins, G.J., Lengauer, C., Vogelstein, B., and Kinzler, K.W. Genes expressed in human tumor endothelium. Science, 289: 1197-1202, 2000.

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Kudos to Hopkins Team
June 30, 2000

John L. Cameron, MD, The Alfred Blalock Professor and Chairman of the Department of Surgery at Hopkins has lead the pancreatic cancer surgery team here at Hopkins for several decades. We are pleased to announce that he has been elected president of the American Surgical Association. The association, established in 1878, is the oldest surgical association in the United States. The presidency of the ASA is regarded as the highest honor one can achieve in American surgery.

Bert Vogelstein, M.D., is the "father" of the modern cancer research effort at Hopkins. Bert is a pioneer of the idea that cancer is a genetic disease. His research focuses on colon cancer, but he he has trained much of, and collaborates extensively with, the pancreas cancer research team. We are pleased to announce that Bert received the General Motors Cancer Research Foundation Charles S. Mott Prize. The award, which includes a $250,000 prize, honors contributions to the discovery of cancer causes or prevention. Vogelstein received the award at a ceremony at the National Institutes of Health.

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Finding a Diamond in the Gravel
June 13, 2000

Some time ago, here in the "What's New" pages, we introduced an analogy. We noted that we get televisions fixed when only a single small part breaks. The same holds for cars, houses, and bicycles. Maybe if we knew just what was broke in a cancer cell, we could fix it.

But how? We've made great progress in understanding what is broke in cancer cells. Yet, how to fix them? Even if it were as easy as car repair, there are problems. When faced with a screw that needs a ratchet, we usually hunt and peck until the right fit is found. After a dozen tries, you are guaranteed to find the one. This may not be such a bad strategy to find the right fit of a drug to the problem of cancer.

In the recent issue of the journal, Cancer Research (June 15), Johns Hopkins researchers from the Kern Laboratory tried this very technique. Hopkins postdoctoral fellow Dr. Gloria Su and resident in surgery Dr. Taylor Sohn tried over 16 thousand chemical compounds, looking for ones that could turn on a specific function that is often broken in pancreatic cancer (e.g., the DPC4 signaling pathway that regulates cell growth). The process was done with very small volumes of cancer cells in culture - over 16 thousand small colonies of cells! Like sifting for diamonds in a pile of gravel, they had to use a special technology to screen through all the cultures, to each of which was added just one of the compounds. A half-dozen promising compounds were identified. One of the compounds turned out to be a novel and specific inhibitor of a protein called HDAC (histone deacetylase). HDAC normally helps to turn off the functioning (the transcription, or expression) of cellular genes. The new compound was termed Scriptaid, a new and more nontoxic member of a class of compounds that is currently under investigation for antitumor effects.

It is a major aim of the Hopkins research effort to expand out efforts in drug screening. We hope to find new approaches to fix the cancer cells by screening for compounds that do specific things, like turning on the broken pathways that normally would regulate the cells of the pancreas. These first attempts are exciting, but like diamonds in the rough, only hint at the gems to be uncovered.

Reference:
Su GH, Sohn TA, Ryu B, Kern SK. A novel histone deacetylase inhibitor identified by high-throughput transcriptional screening of a compound library. Cancer Res 60, 3137-3142, 2000.

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Inactivation of the Breast Cancer Gene (BRCA2) in the Precursors to Invasive Pancreatic Cancer
May 12, 2000

In this month's issue of the American Journal of Pathology, Dr. Michael Goggins and colleagues from Johns Hopkins report an exciting study of the timing of inactivation of the second breast cancer gene (BRCA2) in the early development of pancreatic cancer. Dr. Goggins had previously shown that ~7% of patients with pancreatic cancer, particularly those of Ashkenazi Jewish heritage, developed their cancer because they inherited a mutation in the second Breast Cancer Gene (BRCA2) (see Cancer Research 1996, volume 56, pages 5360-5364). This earlier finding by Dr. Goggins suggests that some patients with pancreatic cancer, particularly those with a strong history of breast cancer, may benefit from genetic testing for mutations in BRCA2. (If you would like to learn more about testing, visit http://www.pbs.org/gene/findout/3_findout.html or http://pathology.jhu.edu/pancreas_genetic_testing).

In the current study, Dr. Goggins and colleagues looked at the timing of BRCA2 inactivation in early pancreatic cancers and they found that this inactivation occurs relatively late (biologically speaking). This important finding by Dr. Goggins and his team may explain why the pancreatic cancers which develop in patients with inherited mutations in BRCA2 arise late in life.

Also in this month's issue is a second article on pancreatic cancer from the Hopkins Scientists. In this article, Dr. Wilentz and colleagues further characterize a newly recognized form of pancreatic cancer called "medullary cancer."

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Hopkins Scientists Make Two Advances Towards Early Detection of Pancreatic Cancer
April 10, 2000

The April 1, 2000 issue of Cancer Research contains two reports on pancreatic cancer from scientists at Johns Hopkins. In the first of these two papers, Dr. Michael Goggins reports that multiple genes are "hypermethylated" in pancreatic cancer.

Methylation refers to the addition of an extra carbon atom to DNA and it is a common mechanism by which cancer preventing (tumor suppressor) genes are inactivated in cancers. Goggins' team (http://pathology.jhu.edu/pancreas/gogginslab) studied a series of 45 pancreatic cancers and, remarkably, they detected hypermethylation in at least 60% of the cancers. Importantly, hypermethylated genes have been used in other organ systems to develop screening tests for cancer. The finding by Goggins and colleagues may help in the development of a new screening test for pancreatic cancer.

Also in the April 1, 2000 issue of Cancer Research, Dr. Robb Wilentz and colleagues from Johns Hopkins report detailed studies on the genetic alteraions in precancerous lesions (called PanINs) in the pancreas. Wilentz et al. demonstrated that loss of the DPC4 tumor suppressor gene occurs late in the development of these precancerous lesions, suggesting that DPC4 loss could be a good marker for a high risk of developing an invasive cancer of the pancreas.

Taken together, these studies help define some of the genetic alterations which, in the future, may be used to develop new screening tests.

References:
Ueki, T., Toyota, M., Sohn, T.A., Yeo, C.J., Issa, J.-P.J., Hruban, R.H., and Goggins, M. Hypermethylation of multiple genes in pancreatic carcinoma. Cancer Res, 60: 1835-1839, 2000.

Wilentz, R.E., Iacobuzio-Donahue, C.A., Argani, P., McCarthy, D.M., Parsons, J.L., Yeo, C.J., Kern, S.E., and Hruban, R.H. Loss of expression of Dpc4 in pancreatic intraepithelial neoplasia: Evidence that DPC4 inactivation occurs late in neoplastic progression. Cancer Res, 60: 2002-2006, 2000.

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Quality of Life and Outcomes After Pancreaticoduodenectomy
February 11, 2000

Pancreaticoduodenectomy has been gaining acceptance as an appropriate procedure for various malignant and benign diseases in and around the pancreas. As experience with pancreaticoduodenectomy grows, there are increasing numbers of pancreaticoduodenectomy survivors who have recovered from their procedure and who live with the requisite altered upper gastrointestinal anatomy. This study represents the largest study ofquality of life in Whipple survivors reported to date. While there is a general impression that pancreaticoduodenectomy can severely impair quality of life and alter normal activities, the results of this study prove otherwise.

A standard quality of life questionnaire and functional outcomes survey was received back from 192 Whipple patients who were operated on at the Johns Hopkins Hospital between 1981 and 1997, inclusive. The quality of life survey assessed 30 items on a visual analog scale, categorized into three domains: physical, psychological, and social. Scores were reported as a percentile, with 100% being the highest possible score. The same quality of life questionnaire was also sent to laparoscopic cholecystectomy patients and to healthy individuals, both to serve as control groups.

The overall quality of life scores for the pancreaticoduodenectomy patients in the three domains (physical, psychological, social) were 78%, 79%, and 81%, respectively. These scores were comparable to those of laparoscopic cholecystectomy patients (scores of 83%, 82%, and 84%, respectively) and healthy controls (scores of 86%, 83%, and 83%, respectively). Assessment of post-pancreaticoduodenectomy functional outcomes indicated that some common problems included early weight loss, abdominal pain, fatigue, and loose stools.

These data provide the largest single institution experience assessing quality of life after the Whipple procedure. Remarkably, these data demonstrate that surviving Whipple patients as a group have near normal quality of life scores. This corrects the general misimpression that Whipple patients have severely impaired quality of life, and cannot return towards normal activities.

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Immunohistochemical Staining for DPC4: From Gene Discovery to Clinical Application
January 10, 2000

In 1996, Dr. Scott Kern and colleagues at Hopkins discovered a new gene which appeared to be selectively inactivated (deleted) in the development of cancer of the pancreas. Dr. Kern and his colleagues named this gene "DPC4" for Deleted in Pancreas Cancer locus 4 (see Science 1996, vol. 271:350-353). The discovery of this gene was exciting because DPC4 is inactivated in a large number of cancers of the pancreas, but also because its inactivation appears to be relatively specific for cancer of the pancreas. That is, DPC4 appears to be only rarely inactivated in other tumor types.

In addition to adding to our understanding of the basic biology of pancreatic cancer, the discovery of the DPC4 gene by the Hopkins team has a number of important clinical applications. For example, in this month's issue of The American Journal of Pathology (Am J Pathol 2000, vol 156:37-43), Robb Wilentz and colleagues from Johns Hopkins report a new immunohistochemical stain for DPC4. This new stain can detect DPC4 in tissue sections (such as biopsies), and the staining pattern directly mirrors the DPC4 gene status. Because of its simplicity and availability, the immunohistochemical staining technique Dr. Wilentz developed for DPC4 has a number of direct clinical applications. For example, staining for DPC4 may help to distinguish benign chronic pancreatitis (which should express DPC4) from cancer of the pancreas (half of which will not express DPC4). Thus, DPC4 staining will add a valuable tool to the interpretation of needle biopsies of the pancreas. In addition, the immunohistochemical assay reported by Wilentz and colleagues for DPC4 may lead to answers in the investigative area. For instance, the immunohistochemical study of early lesions in the pancreas may help determine the stage at which DPC4 inactivation contributes to neoplastic progression and thereby help in the development of new screening tests for early pancreatic cancer.

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