The Sol Goldman Pancreatic Cancer Research Center


Advances and Discoveries Made at Johns Hopkins


Mutations in the BRAF gene found in pancreatic cancer (October 2003):
It has become clear that pancreatic cancer is a disease caused by damage to the DNA (called mutations). The identification of which genes are mutated in pancreatic cancer provides insight into the fundamental nature of the disease. In the October issue of the American Journal of Pathology, Dr. Kern and colleagues report mutations in the BRAF and in the FBXW7 genes. It is hoped that a better understanding of the effects of these mutations will provide insight into why pancreatic cancer is so aggressive.

Am J Pathol. 163:1255-60, 2003



Determining the stage at which selected genes are made in tumors of the pancreas (September 2003):
Just as colon polyps give rise to invasive colon cancer, so too has it become clear that small non-invasive lesions in the pancreas (called PanINs) can give rise to invasive pancreatic cancer. These small non-invasive lesions in the pancreas are exciting, because they represent a curable stage of pancreatic cancer. Dr. Anirban Maitra at Johns Hopkins has studied a large series of "PanINs" and he has defined the stages at which different genes are made by the tumor cells. This finding is exciting because it identifies which genes are the best targets for the development of early detection tests, and which genes are the best targets for the treatment or prevention of early tumors of the pancreas.

Mod Pathol. 16:902-12, 2003



Improving the interpretation of small biopsies of the pancreas (September 2003):
It can be very difficult to biopsy the pancreas, and when the pancreas is biopsied often only a few cells are obtained. As a result, the diagnostic interpretation of pancreatic biopsies can be very difficult. Scientists at Johns Hopkins have identified a group of genes that are made at high levels by pancreatic cancer cells. They then showed that staining small biopsies for two of these markers, PSCA and mesothelin, can greatly improved the accuracy of diagnosis and therefore improve patient care.

Appl Immunohistochem Mol Morphol. 11:238-43, 2003

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New cellular pathway found to be active in pancreatic cancer (September 2003):
Scientists at Johns Hopkins have discovered a cellular pathway that is activated in pancreatic cancer, a finding that provides a potential new way to treat pancreatic cancer. These findings are reported in the journal Nature (the September 14 advanced online publication can be accessed at www.nature.com/nature). This work was performed in the laboratory of Dr. Philip Beachy, who is a Member of the National Academy of Sciences, and a renowned developmental biologist at Johns Hopkins. Dr. Beachy and colleagues demonstrated that the "Hedgehog" pathway is abnormally turned on in many digestive tract tumors, including those of the pancreas. In addition, they have demonstrated that the administration of a drug known as cyclopamine that specifically blocks this pathway in cancer cells results in dramatic reduction of cancer growth. In a mouse model they showed complete and sustained reduction of the tumor following only two weeks of therapy with cyclopamine; most importantly, the mice did not appear to suffer any side effects from the therapy. Although application to humans is years away, the results of this study have potential implications for future treatment options in pancreatic cancers, and demonstrate how knowledge of underlying molecular abnormalities in tumors can lead to new therapies.

Nature

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New Targets for Aberrant Methylation in Pancreas Cancer (July 2003):
Research by Norihiro Sato M.D., Ph.D. in the laboratory of Dr. Michael Goggins has led to the discovery of multiple genes that undergo silencing by DNA methylation (the addition of a carbon group to DNA) in pancreatic cancer. Knowledge of these genes provides us with a better understanding of the role of DNA methylation in pancreatic cancer development. The doctors also showed that these abnormally methylated genes can be detected in pancreatic juice from patients with pancreatic cancer and raising hopes that their detection could aid in the early diagnosis of pancreatic cancer.

Cancer Research (Volume 63, pages 3735-42)

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Pancreatic Cancer Linked to Errant Reactivation of Embryo Cell Pathway (June 2003):
Research by Johns Hopkins Kimmel Cancer Center specialists has uncovered a novel pathway in the origin of pancreatic cancers. The "Notch" pathway, normally turned off in adults, can be turned on after injury to the pancreas.

The findings of Dr. Steven Leach et al. are reported in the June 23, 2003, issue of Cancer Cell.

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Fanconi Gene Abnormalities in Pancreatic Cancer (May 2003):
Dr. Michiel van der Heijden and colleagues studied two of the Fanconi genes: FANCC and FANCG. Inherited and new mutations were found in a number of pancreatic cancers. Some of these mutations are inherited, meaning that these individuals had an increased risk of developing pancreatic cancer because they were born with these mutations in their DNA (they had inherited them from one of their parents. Dr. van der Heijden and colleagues had another interesting finding: three of the nine persons whose pancreas cancer had young onset (less than 50 years of age) had such mutations.

There are no easy tests for the kinds of Fanconi gene mutations now being studied by the researchers, but such tests may become available in the future. Such testing is likely to be of clinical importance. Cells that are defective in the Fanconi genes are known from other research to be highly sensitive to certain chemicals. If may be possible in the future to recommend a different therapeutic regimen for patients with these mutations. More research in this exciting new area is needed.

Cancer Research (Volume 63, 2585-2588)

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Activin Abnormalities in Pancreatic Cancer (March 2003):
Activin receptors play an important "controlling" roll in normal pancreatic cells. Dr. Byungwoo Ryu and colleagues in the Kern Laboratory therefore studied the genes that respond to activin signals to uncover the ways in which the cells are regulated by activin. Using a high-density gene expression screen, they studied gene expression changes characteristic of activin. Some of the genes regulated include genes that directly control cell division. This work was published in the journal Cancer Biology & Therapy, (Volume 2, pages 164-70), and represents the largest study of gene responses to activin published to date.

Also working in Dr. Kern's lab, Dr. Paula Hempen and colleagues found mutations of another form of the activin receptor in pancreatic cancer cells, extending the numbers of tumors known to have abnormalities in the activin system. The newly discovered mutations are in the ACVR2 gene, the activin type 2 receptor. The ACVR2 gene mutations were found in nearly all gastrointestinal tumors that had defects in a DNA-repair pathway involved in familial forms of cancer, including families at high risk of colorectal, pancreatic, and endometrial cancers.

Cancer Research (Volume 63, pages 994-9)

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Anti-Cancer Drug Can Lead to Cancer Invasion (February 2003):
Dr. Sato and colleagues reported an unexpected adverse effect of an anti-cancer drug that is used to remove "methyl" groups (carbon-hydrogen) from DNA. The authors found that this drug can inadvertently switch on certain genes (matrix metalloproteinases) and that the switching on of these genes can promote cancer invasion. This study shows that each therapy needs to be carefully evaluated, because therapies can have unanticipated side effects.

Journal of the National Cancer Institute (Volume 95, pages 327-30)

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