The fundamental hypothesis studied in the basic science research laboratories at Johns Hopkins is that cancer of the pancreas is caused by the accumulation of genetic changes (called mutations) in cancer-causing genes and that an improved understanding of these genetic mutations will lead to new techniques to diagnose and treat this cancer. Our research spans the gamut of pancreatic cancer research and includes:

1. basic science studies of how the pancreas forms embryologically,
2. cutting-edge genetic analyses of surgically resected cancers,
3. studies of why pancreatic cancer runs in some families,
4. research into the precursor lesions that give rise to invasive pancreatic cancer,
5. the development of new screening tests for early pancreatic cancer,
6. the development and testing of new therapies including a novel vaccine-based therapy to treat pancreatic cancer, and
7. studies of advanced/metastatic pancreatic cancer.

Basic Science Embryology
Dr. Steven Leach in the Department of Surgery Dr. Leach directs an NIH-funded research program focused on cell differentiation in pancreas, using both mouse and zebrafish model systems. The research focuses on "epithelial" cells of the exocrine pancreas, the part of the pancreas that makes and transports enzymes that help us digest our food. This work is based on the general hypothesis that pancreatic cancer may be initiated by characteristic changes in epithelial differentiation. By elucidating the molecular mechanisms regulating exocrine differentiation in developing pancreas, Dr. Leach's lab has provided important new insights regarding abnormal differentiation events occurring during the formation of pancreatic cancer. His work has demonstrated critical links between early forms of pancreatic cancer and the epithelium of the embryonic pancreas, providing exciting new strategies for disease detection and chemoprevention.

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Genetic Studies
Dr. Scott Kern in the Departments of Oncology and Pathology has made many of the fundamental genetic discoveries in pancreatic cancer research. He discovered the DPC4 pancreatic cancer gene and helped discover the second breast cancer gene (called BRCA2). Today Dr. Kern's efforts have turned to using our knowledge of the genetic changes in pancreatic cancer to develop new gene-specific therapies. In particular, he has shown that pancreatic cancers with mutations in one of the Fanconi's anemia genes (including BRCA2) are particularly sensitive to certain forms of chemotherapy (mitomycin C).

To learn more about the genetic changes in pancreatic cancer, including a list of changes in the available cell lines, click here.

Dr. Constance Griffin studies the chromosome changes in pancreatic cancer. She reported a chromosome level (karyotyping) analysis of 62 primary adenocarcinomas of the pancreas in an attempt to identify chromosome abnormalities important in this carcinoma. This is the largest number of primary adenocarcinomas of the pancreas which have been studied. Karyotypes were generally complex (more than 3 abnormalities) including both numerical and structural chromosome abnormalities. Many tumors contained at least one marker (unidentifiable) chromosome. Of particular interest, we found double minute chromosomes (DMs) in six tumors; they were observed in 31% of tumors with abnormal chromosomes. DMs are one of two cytogenetic manifestations of gene amplification, and, to our knowledge, these tumors represent the first primary adenocarcinomas of the pancreas with such evidence of gene amplification. Amplification of specific genes has been shown to correlate with a poor prognosis in a number of solid tumors. These genes provide a growth advantage to the tumor, either through action of growth promoting genes, such as oncogenes, or drug resistance genes. Identification of such genes in pancreas cancer would provide important information about its biology.

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Family Studies
Dr. Alison Klein in the Departments of Oncology and Pathology heads the National Familial Pancreas Tumor Registry at Johns Hopkins. Over 1,600 families have joined this registry allowing Dr. Klein to study, in great detail, why pancreatic cancer runs in some families. Just as we get our hair color and eye color from our parents, so too do some individuals appear to inherit an increased risk of developing pancreatic cancer. Dr. Klein has developed a program (called PancPRO) which can be used to calculate this increased risk precisely, and she is now actively hunting for the familial pancreatic cancer gene. Her research includes studies of large populations as well as smaller studies of specific families.

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Precursor Lesions (Photomicrographs of Pancreas Cancer)
Dr. Ralph H. Hruban in the Departments of Pathology and Oncology collaborates extensively with Drs. Kern, Goggins, Iacobuzio, Klein and Maitra. His work has focuses on the study of the earliest precursor lesions (PanINs and IPMNs) which give rise to invasive pancreatic cancers. Just as many colon cancers arise from colon polyps, so too has Dr. Hruban's research helped identify the precursor lesions which give rise to invasive pancreatic cancer. These lesions are important because, unlike invasive pancreatic cancer, these lesions are curable. Our hope is to identify those at risk for pancreatic cancer, to screen them (see below) for these precursor lesions, and then to treat them before they develop an invasive cancer.

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Screening
Dr. Michael Goggins' early detection laboratory at Hopkins is completely dedicated to developing a new screening test for the early detection of pancreatic cancer. Just as there is a PSA test for prostate cancer, so too is Dr. Goggins' lab dedicated to developing an effective screening test for pancreatic cancer. Dr. Goggins and his colleagues have demonstrated that DNA abnormalities shed from pancreatic cancers can be detected in the stool, duodenal fluid and blood of patients with pancreatic cancer. His lab hopes to use the DNA discoveries made by Dr. Kern as the basis for a new screening test. Dr. Goggins is also researching protein biomarkers, as well as abnormalities in DNA methylation as potential early detection tests.

Dr. Akhilesh Pandey is in the McKusick-Nathans Institute of Genetic Medicine and Departments of Biological Chemistry and Oncology. Dr. Pandey's research focuses on the use of mass spectrometry to identify biomarkers in pancreatic cancers. This field of research is known as "proteomics." He also uses bioinformatics, large databases and genome annotation approaches to understand better the causes of pancreatic cancer.

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New Treatments
Drs. Anirban Maitra and Manuel Hidalgo have active research labs focused on using the genetic discoveries made by the Hopkins team to develop better patient treatments. They use a variety of cell culture and animal model systems to test large panels of drugs on large numbers of different pancreatic cancers.

Click here for animation describing vaccine in detail.

Drs. Elizabeth Jaffee and Dan Laheru are developing cancer vaccines for the treatment of pancreatic cancer. They have already developed one particular vaccine in the laboratory that recently completed the initial phase I and II testing. The vaccine was found to be very safe, and they have identified a vaccine dose that appears to be associated with immune activation and prolonged disease-free survival. They are preparing more vaccine for the next phase of testing of this potential new therapy. Their goal is to complete a study of 50 to 75 patients over the next 3 years who have undergone surgical resection of their pancreatic cancer, and to demonstrate a statistically significance difference in disease-free and overall survival. They are also planning to initiate a phase I study combining chemotherapy and the vaccine in patients with advanced pancreatic cancer. From immune cells obtained from patients who appear to have responded to the vaccine, Drs. Jaffee and Laheru can now begin to identify the proteins (antigens) expressed by pancreatic cancers that are recognized by the immune system. For example, they have shown that the cancer cell protein "mesothelin" is a strong activator of the immune system. They have been developing newer vaccine approaches that employ specific antigens and that seem to be more potent than our current approach. We hope to test these new vaccine approaches that employ these antigens in patients within the next 5 years.

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Advanced / Metastatic Disease
Dr. Christine Iacobuzio-Donahue studies pancreatic cancer that has spread beyond the pancreas. In 2003, she created the Gastrointestinal Cancer Rapid Medical Donation Program (GICRMDP) at Johns Hopkins. The participation of a remarkable group of volunteers who consented to a rapid autopsy has allowed Dr. Iacobuzio-Donahue to establish a unique collection of pancreatic cancers that have spread ("metastasized") to organs beyond the pancreas. By comparing these metastatic pancreatic cancers to early non-metastatic pancreatic cancers, dr. Iacobuzio-Donahue hope to understand why some pancreatic cancers behave so aggressively. In so doing she hopes to develop new drugs to specifically target late stage pancreatic cancers.

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References

1. Caldas C, Hahn SA, da Costa LT, Redston MS, Schutte M, Seymour AB, Weinstein CL, Hruban RH, Yeo CJ, Kern SE: Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nat Genet 8:27-32, 1994.
2. Goggins M, Shekher M, Kenan T, Yeo CJ, Hruban RH, Kern SE: Genetic alterations of the transforming growth factor receptor genes in pancreatic and biliary adenocarcinomas. Cancer Res 58:5329-5332, 1998.
3. Goggins M, Schutte M, Lu J, Moskaluk CA, Weinstein CL, Petersen GM, Yeo CJ, Jackson CE, Lynch HT, Hruban RH, Kern SE: Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas. Cancer Res 56:5360-5364, 1996.
4. Goggins M, Offerhaus GJA, Hilgers W, Griffin CA, Shekher M, Tang D, Sohn TA, Yeo CJ, Kern SE, Hruban RH: Pancreatic adenocarcinomas with DNA replication errors (RER+) are associated with wild-type k-ras and characteristic histopathology: poor differentiation, a syncytial growth pattern, and pushing borders suggest RER+. Am J Pathol 152:1501-1507, 1998.
5. Hahn SA, Schutte M, Hoque ATMS, Moskaluk CA, daCosta LT, Rozenblum E, Weinstein CL, Fischer A, Yeo CJ, Hruban RH, Kern SE: DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 271:350-353, 1996.
6. Hruban RH, van Mansfeld ADM, Offerhaus GJA, van Weering DHJ, Allison DC, Goodman SN, Kensler TW, Bose KK, Cameron JL, Bos JL: K-ras oncogene activation in adenocarcinoma of the human pancreas. A study of 82 carcinomas using a combination of mutant-enriched polymerase chain reaction analysis and allele-specific oligonucleotide hybridization. Am J Pathol 143:545-554, 1993.
7. Redston MS, Caldas C, Seymour AB, Hruban RH, da Costa L, Yeo CJ, Kern SE: p53 mutations in pancreatic carcinoma and evidence of common involvement of homocopolymer tracts in DNA microdeletions. Cancer Res 54:3025-3033, 1994.
8. Rozenblum E, Schutte M, Goggins M, Hahn SA, Panzer S, Zahurak M, Goodman SN, Sohn TA, Hruban RH, Yeo CJ, Kern SE: Tumor-suppressive pathways in pancreatic carcinoma. Cancer Res 57:1731-1734, 1997.
9. Schutte M, Hruban RH, Geradts J, Maynard R, Hilgers W, Rabindran SK, Moskaluk CA, Hahn SA, Schwarte-Waldhoff I, Schmiegel W, Baylin SB, Kern SE, Herman JG: Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas. Cancer Res 57:3126-3130, 1997.
10. Su GH, Hilgers W, Sheker MC, Tang DJ, Yeo CJ, Hruban RH, Kern SE. Alterations in pancreatic, biliary, and breast carcinomas support MKK4 as a genetically targeted tumor suppressor gene. Cancer Res 58:2339-2342, 1998.
11. Su GH, Hruban RH, Bansal RK, Bova GS, Tang DJ, Sheker MC, Westerman AM, Entius MM, Goggins M, Yeo CJ, Kern SE. Germline and somatic mutations of the STK11/LKB1 Peutz-Jeghers gene in pancreatic and biliary cancers. Am J Pathol 154:1835-1840,1999.