The Sol Goldman Pancreatic Cancer Research Center


Advances and Discoveries Made at Johns Hopkins


Careful Pathologic Examination Can Be Used to Predict Outcome for Patients with Mucinous Cystic Tumors:
Mucinous cystic tumors are rare neoplasms of the pancreas characterized by the presence of large cysts (fluid filled cavities) lined by mucin producing cells. Some investigators have suggested that all mucinous cystic neoplasms are malignant (capable of spreading to other organs) and that all mucinous cystic tumors should therefore be designated as cancers - "mucinous cystadenocarcinomas."

Robb Wilentz at Johns Hopkins studied over 60 of these rare tumors and found that with careful examination they could accurately separate mucinous cystic tumors into two groups - those that are entirely benign (the tumors never recurred) if completly resected ("mucinous cystadenomas") and those that had a malignant or cancerous potential ("mucinous cystadenocarcinomas"). Importantly, two-thirds of the mucinous cystic tumors in Dr. Wilentz's study fell into the entirely benign group.

Why is this important?
This study demonstrates that simply lumping all mucinous cystic tumors into the malignant category would have incorrectly labeled two-thirds of the patients as having cancer when they didn't!

The study is also important because it highlights the impact private donations can have on research. Dr. Wilentz conducted this research during a research fellowship year he spent in the laboratory of Dr. S. Kern and this fellowship was supported by the Helen S. Heller and Daniel Kim Memorial Funds for pancreatic cancer research at Hopkins. Without this private support, Dr. Wilentz would not have been able to do his study. Private giving makes a difference!

American Journal of Surgical Pathology 23:1320-1327,1999



Peutz-Jeghers Gene Plays a Role in Pancreatic Cancer:
Twelve years ago doctors at Johns Hopkins reported that patients with a rare syndrome, called "The Peutz-Jeghers Syndrome," had an increased risk of developing pancreatic cancer. The reason for this increased risk remained a mystery until now.

The Peutz-Jeghers Syndrome is rare inherited syndrome in which affected patients develop dark pigmented spots on their lips ("mucocutaneous melanin macules") and polyps in their intestinal tract ("hamartomas"). These patients have an increased risk of cancer, expecially pancreatic cancer. Gloria Su, Ph.D. and colleagues from Johns Hopkins uncovered the genetic basis for this association.

The STK11/LKB1 gene in chromosome 19 is responsible for the Peutz-Jeghers Syndrome. Gloria Su and colleagues examined the status of the STK11/LKB1 gene in a large series of pancreatic cancers and in pancreatic cancer resected from patients with the Peutz-Jeghers Syndrome. They found that the STK11/LKB1 gene was inactivated in 4-6% of the pancreatic cancers. While the inactivation of this gene plays a role in only a small percentage of pancreatic cancers, Gloria Su and colleagues made a second, quite remarkable discovery. They found that the inactivation of the STK11/LK1 gene in patients with the Peutz-Jeghers Syndrome explained the development of pancreatic cancer in these patients.

Why is this important?
These findings solve a long-standing mystery. The inheritance of a defective copy of the STK11/LKB1I gene causes the Peutz-Jeghers Syndrome and the inactivation of this gene in these patients explains their increased risk of pancreatic cancer.

American Journal of Pathology 154(6):1835-1840,1999

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Radical Whipple is Safe
Surgical resection is currently the most effective treatment for cancer of the pancreas. The extent of the surgery which should be performed is, however, controversial. Some have argued that the standard pancreaticoduodenectomy (Whipple procedure) should be extended to include the removal of the distal stomach (distal gastrectomy) as well as the removal of additional lymph nodes (retroperitoneal lymphadenectomy). The more extended surgery is called a "radical pancreaticoduodenectomy". The controversy over standard versus radical Whipple has been difficult to resolve, because most centers do one surgery or the other and data between institutions may not be comparable.

In the May 1999 issue of the Annals of Surgery, Drs. Yeo, Cameron and colleagues from Johns Hopkins report a study that may finally help resolve this controversy. They reported a randomized single-institution trial in which patients were randomized to receive either a standard or a radical Whipple. Of the 114 patients randomized, 56 underwent a standard Whipple and 58 a radical Whipple. Dr. Yeo and colleagues found that the two procedures can be performed with similar morbidity and mortality. Importantly, the one-year survival rate for both groups was similar (~80%).

Why is this important?
This important study will continue and the patients enrolled will be followed to determine if there are any long-term benefits to doing a radical Whipple. For now, part of the controversy in the radical versus standard Whipple debate has been answered. Both can be performed with equal morbidity and mortality, but the radical Whipple does not provide any improvement in survival at one year.

DPC4 Pathway Targeted in Pancreatic Cancer
Drs. Michael Goggins and Jaile Dai in Scott Kern's laboratory extensively studied the DPC4 pathways in pancreatic cancer using modern genetic techniques. Dr. Goggins found that the "TGF-ß receptors" can be targeted in pancreatic cancer and Dr. Dai discovered that if he took cells that made no DPC4, and then genetically engineered the cells so that they would produce DPC4, then the cells grew much slower. He also showed that activated DPC4 can kill selected cancer cells.

Why is this important?
These studies provide a clearer understanding of just how pancreatic cancer cells come to misbehave. An understanding of "what's broken" in pancreatic cancers should, in turn, lead to new methods to treat the disease.

Proceedings of the National Academy of Sicence 96:1427-1432,1999
Cancer Research 58:5329-5332,1998

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YEAR 1998

New Type of Pancreatic Cancer
Michael Goggins identified a new type of pancreatic cancer called "Medullary Cancer". This new type of pancreatic cancer has a very specific appearance under the microscope, and Mike has discovered that medullary cancers have an usual pattern of genetic changes called "microsatellite instability".

Why this is important?
Patients with this newly recognized type of pancreatic cancer may have a better prognosis than patients with typical pancreatic cancer, and they may also respond to different types of chemotherapy. Furthermore, because this newly recognized type of cancer has an unusual genetic change associated with it, it may be possible to detect these cancers using genetic tests.

Am J Path 152:1501-1507,1998

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Familial Pancreatic Cancer
Ralph Hruban established the National Familial Pancreas Tumor Registry at Hopkins in 1994. Over 350 families have enrolled in this registry. These include a family in which five brothers and sisters died of pancreatic cancer and seven families in which three generations have been affected. Analysis of the families enrolled in this registry has demonstrated that genetic changes cause pancreatic cancer to run in some families. Just as children inherit their hair color and eye color from their parents, so too do some inherit an increased risk of developing pancreatic cancer.

Why is this important?
As the genetic changes responsible for familial pancreatic cancer are uncovered, family members can be tested to see if they are at risk. Furthermore, because they have such a high risk of developing pancreatic cancer, these families will be the first to benefit from new screening tests for pancreatic cancer.

Surg Onc Clin North Am 7:1-23,1998

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Surgery For Pancreatic Cancer
Surgeons at Hopkins have worked hard to improve the surgical approach to tumors of the pancreas. Thanks to their efforts the Whipple operation (removal of the head of the pancreas) is now a safe option for many patients. In fact more Whipple procedures are performed every year at Hopkins than any other hospital in the world.

Why is this important?
The impact of improved surgery on the pancreas has been dramatic. Operative mortality rates have dropped from over 20% to less than 2% at Hopkins. Remarkably, because more patients are now coming to Hopkins, these improvements at Hopkins have led to a significant decrease in hospital mortality in the entire state of Maryland for pancreatic surgery.

Annals of Surgery 228: 71-78, 1998
Annals of Surgery 227:821-831, 1998
Annals of Surgery 226:248-260, 1997

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YEAR 1997

Pancreas Cancer Vaccine
Elizabeth Jaffee at Hopkins has developed a novel vaccine for the treatment of pancreatic cancer. Dr. Jaffee has used two cancers resected from patients at Hopkins to develop this vaccine. After the cancers were grown and cultured, she used a virus to introduce a new gene into the cancer cells. This new gene called "Granulocyte - Macrophage Colony Stimulating Factor" was incorporated into the cancer cells and it codes for a factor which actively stimulates the body's immune system. These cultured cancer cells are then used to produce a live anti-pancreas cancer vaccine. This vaccine has already been tested on 15 patients with pancreatic cancer in a Phase I clinical trial. Although early in the testing process, Dr. Jaffee has already seen positive skin reactions in vaccinated patients.

Why is this important?
This is a completely new approach to the treatment of pancreatic cancer. Should it prove effective, it will harness the body's immune system against the cancer without causing the side effects of chemotherapy. Importantly, Dr. Jaffee has been studying the immune reaction of patients vaccinated with this vaccine and hopes to use these studies to develop a second generation of pancreatic cancer vaccines.

Cancer Research 57:1537-1546, 1997.
The Cancer Journal from Sci Am 4:194-203, 1998

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Genetic Profile of Pancreatic Cancer
Ester Rosenblum in Scott Kern's laboratory has characterized the genetic profile of pancreatic cancer. This includes mutation (DNA changes) in multiple genes, including the K-ras, p16, p53, DPC4, BRCA2, LKB1, MKK1 and TGF Beta receptor genes.

Furthermore, Robb Wilentz and Carlos Caldas have demonstrated, using the technique of PCR (polymerase chain reaction - the equivalent to a genetic xerox machine), that some of these genetic changes (such as K-ras) can be detected in the duodenal fluid and/or stool of patients with pancreatic cancer.

Why is this important?
An understanding of the genetic profile of pancreatic cancer will allow scientists to develop new drugs to treat pancreatic cancer, and, because these genetic changes can be detected in stool these discoveries will lead the way to new screening tests to detect early pancreatic cancers. Just as colon cancer can now be detected by testing stool for blood, so too do we envision detecting pancreas cancer by testing stool samples for genetic changes.

Cancer Research 57:1731-1734, 1997

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Precursors to Pancreatic Cancer
Dan Brat and Robb Wilentz have examined a large series of resected pancreatic cancers and they have identified the precursor lesions to cancer of the pancreas. Called "Duct Lesions" these precursors arise in the smallest pancreatic ducts. They probably arise years before the patient develops an infiltrating cancer and many years before they develop any symptoms. Hopkins scientists have characterized these under the microscope, and they have also studied these duct lesions at the genetic level. This two-pronged approach to the study of duct lesions has established that duct lesions are indeed the elusive precursor to pancreatic cancer.

Why is this important?
This important findings represents a first step towards the development of new tests to detect pancreatic cancer at very early stages. If we are to be effective in treating pancreatic cancer we must detect it before the "Horse out of the barn."

Cancer Research 57:2140-2143, 1997.
Am J Surg Pathol 22:163-169, 1998

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YEAR 1996

DPC4
Stephen Hahn in Scott Kern's laboratory at Hopkins discovered the DPC4 (Deleted in Pancreas Cancer 4) gene on chromosome 18 and he demonstrated that this gene is mutated (missing) in approximately half of all pancreatic cancers. In the other half of the cancers, DPC4 is harder to turn on, due to other gene defects. Remarkably, the mutation of DPC4 appears to be relatively specific for pancreatic cancer.

Why is it important?
DPC4 is the first gene which appears to specifically altered in pancreatic cancer. Now that it has been identified scientists at Hopkins are working to understand how DPC4 works so that they can develop new drugs to "replace" the missing DPC4 function in pancreatic cancers.

Science 271:350-353, 1996
Cancer Research 56:2527-2530, 1996

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The Breast Cancer Gene (BRCA2)
The second breast cancer gene (called "BRCA2") was discovered because of a remarkable advance made by the Johns Hopkins pancreas cancer research team. Mieke Schutte in Scott Kern's lab used a revolutionary technique called "RDA" to study a pancreas cancer removed by surgeons at Johns Hopkins. She discovered that this cancer was missing a small piece of DNA from chromosome 13. This piece of DNA was the second breast cancer gene. Michael Goggins extended these and found that as many as 7% of patients with pancreas cancer get their cancer because they inherit had a defective copy of the BRCA2 gene. These patients were born with a defective copy of the BRCA2 gene and they inherited this defective copy from one of their parents.

Why is this important?
This discovery is quite remarkable because it suggests: (1) that there is a link between pancreas and breast cancer; and (2) that patients with a family history of breast and pancreas cancer can now be tested to see if they carry this gene.

Proc Natl Acad Sci USA 92:5950-5954, 1995.
Cancer Research 56:5360-5364, 1996

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YEAR 1995

Chromosome Changes Associated with Pancreas Cancer
Connie Griffin has applied "classical cytogenetics" (a test performed on fluids obtained by amniocentesis from pregnant women to determine the health of their babies) to visualize and examine individual chromosomes in pancreatic cancers. She examined a large number of pancreatic cancers using this technique and has identified recurring chromosome changes in these tumors. These include losses of specific chromosome, and gains of other portions of chromosomes. These studies provide an important advance in our understanding of the genetic changes responsible for the development of cancer of the pancreas.

Why is it important?
Because genes sit on chromosomes, the cytogenetic analysis of cancers can lead to the discovery of genes important of the development of the cancer. It is our hope that further analysis of the recurrent chromosome changes identified by Connie Griffin, will lend to the identification of additional yet undiscovered genes responsible for cancer of the pancreas. Once discovered an understanding of the function of these genes may lead to new ways to diagnose and treat pancreatic cancers.

Cancer Research 55:2394-2399, 1995
Am J Pathol 150:383-391,1997.

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SAGE
Victor Velculescu in Ken Kinzler's laboratory developed a revolutionary technology called "SAGE" (serial analysis of gene expression). SAGE is a powerful technique which can be used to identify and quantify all genes expressed in a tissue. When the investigators applied SAGE to pancreatic cancer they were able to identify a total of 404 "transcripts" expressed at high levels in pancreatic cancers (transcripts are pieces of RNA which code for proteins (also called antigens) that might be released into the blood). The identification of these transcripts is an important advance, because any one of the 404 may form the basis for a new screening test. In an effort to share this exciting data the Hopkins investigators have established a Web page on which they freely share all of their SAGE findings (http://welchlink.welch.jhu.edu./~molgen-g/home.htm).

Why is this important?
This is the first step in developing a completely new screening test for pancreatic cancer. For example, prostate cancers make "prostate specific antigen" which is detectable in the blood and which forms the basis for the current screening test for the early detection of prostate cancers. The application of SAGE technology to pancreatic cancers is the first step in developing such a test for the pancreas. We hope to find a "pancreas specific antigen".

Science 270:484-487, 1995
Science 276:1268-1272, 1997

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YEAR 1994

Role of p16
Carlos Caldas in Scott Kern's laboratory was the first to demonstrate the role of p16 gene in the development of pancreatic cancer. Christopher Moskaluk extended these studies and demonstrated that some cases of inherited pancreatic cancer, particularly those associated with melanoma, are caused by inherited mutations (defects) in the p16 gene. Dr. Moskaluk also showed that p16 is defective in many of the earliest forms of pancreatic cancer, providing a clue as to how the disease develops.

Why this is important?
Family members from families in which there is a strong history of pancreatic cancer and melanoma can now be tested for inherited defects in the p16 gene. Carriers of the p16 defects can be screened more carefully for pancreatic cancer and melanoma, while those found not to carry the p16 defect will be relieved of their anxiety.

Nature Genetics 8:27-32,1994

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