The Sol Goldman Pancreatic Cancer Research Center

Advances and Discoveries Made at Johns Hopkins

New Technology Developed for the Early Detection of Pancreatic Cancer:
There are no early warning signs of pancreatic cancer and there are no early detection tests. As a result, most patients are not diagnosed until after the cancer has spread. Just as there is a PSA test for prostate cancer, so too do we urgently need an early detection test for pancreatic cancer. Dr. James Eshleman at Hopkins has recently developed a new technology that can detect rare DNA mutations (alterations in the DNA sequence) even when these mutations are admixed with much larger numbers of normal DNA sequences (Nat Methods. 2004 Oct 21;1(2):141-147 ). The technology, called "LigAmp" detected the most common mutation found in pancreatic cancer (KRAS2 gene mutations) even when a single mutant KRAS2 gene was admixed with 1,000 normal genes. Dr. Eshleman and colleagues have further shown that LigAmp can be used to detect DNA mutations shed from pancreatic cancers in pancreatic juice samples.

Nat Methods. 1:141-7, 2004

Applying new bioinformatics technology to discover new markers of pancreatic cancer (November and December 2004):
The cloning of the human genome has opened the door to global analyses of gene expression in pancreatic cancer on a scale not imaginable a few years ago. These analyses can help identify literally hundreds of genes that are made at high levels by pancreatic cancer cells. All too often however, the analyses produce potentially interesting gene sequences but the identity of the gene for which these sequences code for has not been identified. Akhalesh Pandey at Johns Hopkins has used cutting edge bioinformatics tools to identify a number of exciting genes that are overexpressed in pancreatic cancer. These genes are potential targets for new therapies and for the early detection of pancreatic cancer.

Cancer Biology and Therapy November 2004
Cancer Biology and Therapy December 2004


New proteomic markers of pancreatic cancer found (September 2004):
Proteomics is the study of all of the proteins in a tissue or fluid. Dr. Akhelesh Pandey carried out a comprehensive characterization of the "pancreatic juice proteome" in patients with pancreatic adenocarcinoma. A total of 170 unique proteins were identified including known pancreatic cancer tumor markers (e.g., CEA, MUC1) and proteins overexpressed in pancreatic cancers (e.g., hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein (HIP/PAP) and lipocalin 2). In addition, he identified a number of proteins that have not been previously described in pancreatic juice (e.g., tumor rejection antigen (pg96) and azurocidin). The proteins identified in this study will be further assessed for their potential as biomarkers for pancreatic cancer by quantitative proteomics methods or immunoassays.

J Proteome Res. Sep-Oct; 3(5):1042-55, 2004


Exploiting BRCA2 gene mutations to treat pancreatic cancer (August 2004):
Nine years ago, the Kern Laboratory found mutations of a new gene, called BRCA2. Soon, this laboratory and others working in other tumor systems found that mutations of the gene were often inherited, raising the risk for pancreatic, ovarian, and breast cancer when an individual inherits one bad copy of the gene. This was the second gene found to cause inherited breast cancer, thus leading to the gene name, BRCA2. Dr. Kern's postdoctoral fellow Michiel van der Heijden followed up on this earlier discovery and showed that that pancreatic cancer cells with BRCA2 gene mutations are especially susceptible to the anticancer drugs mitomycin and cis-platin. Based on this exciting finding, it may be possible in the future to recommend individualized therapeutic regimens for patients with these mutations. More research, and possibly even a clinical trial, in this new area are underway.

Am J Pathol. 165:651-7, 2004


Immune target for the treatment of pancreatic cancer discovered (August 2004):
Dr. Elizabeth Jaffee has developed a novel whole cell vaccine to treat patients with pancreatic cancer. She has previously found that this vaccine treatment produces an anti-tumor immune response in some patients. In the August issue of the Journal of Experimental Medicine, Dr. Jaffee reports that she has discovered a protein, mesothelin that appears to be responsible for the anti-tumor effect seen with the whole cell vaccine. Mesothelin is an antigen demonstrated previously by gene expression profiling to be up-regulated in most pancreatic cancers, and Dr. Jaffee found the consistent induction of CD8(+) T cell responses to mesothelin in patients who responded to the vaccine. This finding not only provides insight into the immune mechanisms underlying anti-tumor responses, but it is also hoped that it will lead to new "peptide" based vaccines that are cheaper and easier to administer than the whole cell vaccine.

Journal of Experimental Medicine, 2004


Using endoscopic ultrasound (EUS) to screen for early pancreatic cancer in asymptomatic patients (July 2004):
In the July issue of Clinical Gastroenterology Hepatology, Dr. Marcia Canto and colleagues from Johns Hopkins report the results of screening for pancreatic cancer in asymptomatic (patients without symptoms) individuals known to be at increased risk because of their family history. Endoscopic ultrasound (EUS) was used. In this technique a small tube with an ultrasound device at the end is inserted through the patient's nose and into the patient's stomach and duodenum. The ultrasound device can then be used to image the pancreas. Thirty-eight patients were screened in Dr. Canto's study and six pancreatic masses were found. Several of these patients went to surgery and one was found to have an early cancer and another a precancerous tumor (intraductal papillary mucinous neoplasm). Therefore, 5.3% or 1 in 20 patients was found to have a clinically important pancreatic mass. This study therefore represents the first step towards demonstrating that screening for early pancreatic cancer is possible.

Clin Gastroenterol Hepatol 2(7):606-21, 2004


The risk of pancreatic cancer increases if you have more relatives with pancreatic cancer (April, 2004):
Dr. Klein and colleagues followed 838 families who participate in the National Familial Pancreatic Tumor Registry at Johns Hopkins to determine how if new pancreatic cancers are more likely to develop in families in which more than one family member has been diagnosed with pancreatic cancer. Twenty-two new pancreatic cancer cases developed in these families after the family had entered the registry. Dr. Klein found that individuals with three or more first-degree relatives with pancreatic cancer (brothers, sisters, parents or children) had a 32-fold increased risk of developing pancreatic cancer. Individuals with two first-degree relatives with pancreatic cancer had a 6.5-fold increased risk. This increase in risk was even higher among family members who smoked cigarettes. The results of this study further establish that pancreatic cancer does cluster in families. Additionally, these results help to identify individuals who may benefit from screening for the early signs of pancreatic cancer once reliable screening tests are developed.

Cancer Research 64:2634-2638, 2004


Two potential new blood markers of pancreatic cancer (March and April 2004):
New blood markers for the early detection of pancreatic cancer are urgently needed. Just as there is a PSA test for prostate cancer, so too do we need a test for pancreatic cancer. Dr. Goggins' lab is dedicated to the discovery of these markers and in 2004 he reported the discovery of two new promising markers, osteopontin and MIC-1. These markers were identified in previous studies of gene expression using "gene chip" analysis of surgically resected cancers, and Dr. Goggins went on to show that both MIC-1 and osteopontin are released into the blood and that the blood levels of these markers are higher in patients with pancreatic cancer than they are in patients without cancer. Both markers were significantly better than the previous "gold standard" CA 19-9.

Cancer Epidemiol Biomarkers Prev. 13:487-91, 2004
Clin Cancer Res. 10(7):2386-92, 2004


Improved understanding of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas (March 2004):
Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are being diagnosed with growing frequency, but these distinctive tumors of the pancreas have not been well-characterized. Dr. Goggins and coworkers used cutting edge oligonucleotide microarrays to analyze the genes made ("the gene expression profile") by a series of IPMNs. They identified four genes that appeared to be highly associated with the presence of an invasive adenocarcinoma. Notably, the expression of at least two of the four genes was observed in 73% of 22 invasive IPMNs but in none of 16 noninvasive IPMNs (P < 0.0001). These findings suggest that preoperative assessment of gene expression profiles may be able to differentiate invasive from noninvasive IPMNs. They have also performed a similar analyses on another type of tumor in the pancreas called "mucinous cystic neoplasm."

Am J Pathol. 164(3):903-14, 2004
Oncogene. Oct 18, 2004.


Series of advances made by Dr. Iacobuzio-Donahue's lab (Spring 2004):
Dr. Iacobuzio-Donahue recently published two exciting articles in Cancer Research. The first article, published in the December 15 issue (Cancer Research 2003; 63:8614-22) describes the largest, most comprehensive study to date of gene expression (the genes made) in pancreatic cancer. Close to 100 samples were analyzed using the most current gene chip (Affemetrix U133). Dr. Iacobuzio-Donahue and colleagues discovered 142 potential new markers of pancreatic cancer. Already, Dr. Koopmann has shown that one of these markers, called "osteopontin," is elevated in the blood of patients with pancreatic cancer (Cancer Epi Biomarkers Prev, 2004; 13:487-91) and Dr. Nichols has demonstrated that another of these markers, claudin 4, may be a useful therapeutic target (Am J Clin Pathol. 2004; 121:226-30).

In the second paper published by Dr. Iacobuzio-Donahue (Cancer Research 2004; 64:871-875) she describes the largest genetic analysis conducted to date of the DNA changes in pancreatic cancer. Dr. Iacobuzio-Donahue and colleagues conducted a large-scale "allelotypes" (an analysis of DNA losses in a cancer) on a series of pancreatic cancers and they discovered a number of hot spots of DNA alterations in pancreatic cancer. These hot spots will help other scientists identify the genes that are targeted for inactivation in pancreatic cancer. An understanding of these genes, in turn, may lead to a better understanding of why pancreatic cancer develops and how to treat it.

Cancer Res. 64: 871-875, 2004
Cancer Epidemiol Biomarkers Prev. 13:487-91, 2004
Clin Cancer Res. 10:1597-1604, 2004
Am J Clin Pathol. 121(2):226-30, 2004