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While scientists have made great strides in advancing our understanding of pancreatic ductal adenocarcinoma, little is known about rarer tumors that arise in the pancreas. In this month's issue of the American Journal of Pathology, S. Abraham and colleagues from Johns Hopkins report a detailed molecular genetic analysis of pancreatoblastomas. Pancreatoblastoma is a rare pancreatic tumor with a distinctive microscopic appearance that generally affects infants and young children (see the FAQ section of this Web site for more information on pancreatoblastomas and other rarer variants of pancreas cancer- http://pathology2.jhu.edu/pancreas/typtable.cfm). Dr. Abraham analyzed a series of nine pancreatoblastomas for genetic alterations (changes in the DNA sequence of the tumors). She found three interesting things. First, pancreatoblastomas are genetically very different from the more common ductal adenocarcinomas of the pancreas. Most ductal adenocarcinomas harbor mutations in the k-ras, p53 and DPC4 genes, while pancreatoblastomas do not. Instead, pancreatoblastomas show alterations (mutations) in the beta-catenin/APC genes. 2) Dr. Abraham also showed that chromosome 11p is frequently altered in pancreatoblastomas. Chromosome 11p is frequently altered in hepatoblastomas (a rare pediatric tumor in the liver), suggesting that pancreatoblastomas are more closely related to hepatoblastomas than they are to pancreatic ductal adenocarcinomas. 3) Finally, one of the patients included in Dr. Abraham's series of pancreatoblastomas had the clinical syndrome called "familial adenomatous polyposis" or "FAP". Patients with familial adenomatous polyposis develop numerous polyps in their colon at an early age and Dr. Abraham demonstrates that they can also develop pancreatoblastomas.
Dr. Abraham's study is an important advance in our understanding of some of the rarer variants of pancreas cancer. Dr. Abraham's paper is available on-line at: http://ajp.amj pathol.org/cgi/content/full/159/5/1619
In this week's issue of the Journal of American Medical Association (JAMA), Drs. Michaud, Giovannucci, Willett, Colditz, Stampfer, and Fuchs from the Harvard School of Public Health and the National Cancer Institute report a large study of pancreatic cancer risk. They used two large groups of patients - the Health Professions Follow-up Study and the Nurses Health Study to determine the risk factors of pancreatic cancer. A total of 46,648 men and 117,041 women were free prior cancer at baseline were followed for 10-20 years. Remarkably, the authors found that decreased physical activity, obesity, and being tall increased the risk of pancreatic cancer. The effect of increased physical activity on decreasing the risk of pancreatic cancer was the greatest among those who are overweight. The association between obesity and physical activity and the risk of pancreatic cancer was explained, biologically, by the association of abnormal glucose (sugar) tolerance and pancreatic cancer.
While additional studies are needed, this large epidemiologic study certainly suggests that increased physical activity and weight reduction are reasonable measures that may, in addition to reducing one's risk of heart disease, reduce the risk of pancreatic cancer.
Reference Dr. Ryu and colleagues in Dr. Kern's laboratory for pancreatic cancer
research at Johns Hopkins searched for such genes. Dozens of
invasion-specific markers were identified in invasive pancreatic cancers
obtained from patient samples. Many of these were new markers not
previously considered as cancer markers, and many of the genes are
expressed not by the tumor cells but instead by the patient's response to
the tumors. Some of these markers are known to be secreted and to be
detectable in simple blood samples. A strong effort is underway to examine
these candidates and develop markers for use in reliable assays for cancer
that can be done on serum, to aid medical imaging, and to serve as targets
for the development of invasion-specific anticancer therapy. The first
such candidate marker was the subject of a recent paper by Argani and
colleagues (See What's New, June 2001)
Reference Because of the need to understand these signals, there has been a great
effort to identify genes that are mutated and turned off in tumors. These
are the tumor-suppressor genes. The inactivation of these genes allows
tumors to escape from the normal growth controls that the surrounding
cells and tissue are trying to place on them.
Activin is a protein secreted by normal cells. To exert its action,
activin must bind receptors on a cell. The receptors propagate a signal to
the cell, but it was not previously known that these signals were able to
suppress tumor growth. Mutations within the activin receptor gene were
found recently in some pancreatic cancers by Dr. Gloria Su and colleagues
in Dr. Kern's laboratory for pancreatic cancer research at Johns Hopkins.
In tumors that lack the mutations, someday it might be possible to
administer activin as a therapeutic strategy. It might also be possible
to mimic the effects of activin on tumor cells by a precise molecular
targeting using specially designed new drugs that directly activate the
signal pathway without the need for intact receptors. This is a new idea
that was previously unknown, but now can be explored. It is our hope that
one can design a rational therapy that would specifically attack the most
vulnerable components of pancreatic cancer.
These findings are exciting for several reasons. First, they
demonstrate the power of new technologies such as SAGE to discover new
tumor markers. Second, PSCA, because it is selectively overexpressed in
pancreatic cancers, maybe a useful marker for pancreatic cancer. Third,
other groups have shown that PSCA can be an immune target and therefore
PSCA is being explored as a target for the immune treatment of cancers.
The demonstration of PSCA expression in pancreatic cancer suggests a new
avenue for treating pancreatic cancers. That is, immunotherapy directed at
cells expressing PSCA. On an important side note, this work was supported, in large part, by
generous donations from the friends and family of Michael Rolfe (
http://pathology2.jhu.edu/pancreas/mrolfe.htm) demonstrating the power of
private giving to advance pancreatic cancer research.
In the current issue of Clinical Cancer Research
(http://clincancerres.aacrjournals.org/cgi/content/full/7/3/738), A.
Tersmette and colleagues from Johns Hopkins report that first-degree
relatives (brothers and sisters, parents and children) of patients with
"familial pancreatic cancer" have a significantly increased risk of
developing pancreatic cancer. Tersmette and colleagues followed 341
families enrolled in the National Familial Pancreas Tumor Registry
NFPTR)
and found that the first-degree relatives of
familial pancreatic patients had an 18-fold increased risk of developing
pancreatic cancer when compared to the general population (the "SEER"
database). In this study, familial pancreatic cancer was defined as at
least a pair of first-degree relatives with pancreatic cancer in a family.
Remarkably, if there were three or more family members with pancreatic
cancer when the family enrolled in the NFPTR, then the risk of other
family members developing pancreatic cancer jumped to 57-fold greater than
the general population.
This study firmly establishes that "Familial Pancreatic Cancer" is a real
entity and it provides a quantitative measure of the risk of pancreatic
cancer in these families. Importantly, studies such as this will form the
basis for identifying individuals at-risk for developing pancreatic cancer
who might benefit from new screening tests as they are developed. If
you have a strong family history of pancreatic cancer and would like to
join the research studies currently underway at Hopkins, please consider
joining the NFPTR. If you would like to join, please contact the
Coordinator of the NFPTR, Kieran Brune (kbrune@jhmi.edu).
Reference *In order to evaluate the effectiveness of the vaccine, a
60 patient study is planned to begin in May, 2001. As much
as we would like to offer the vaccine to everyone, eligibility criteria
had to be established for this study. Patients with adenocarcinoma of the
pancreas who have surgery Johns Hopkins Hospital to remove their pancreas
cancer and who have no clinical evidence of spread of the cancer outside
the pancreas will be eligible for this study. Patients with bile duct
cancer or neuroendocrine tumors or islet cell cancer are not eligible.
Please contact Dr. Elizabeth Jaffee (ejaffee@jhmi.edu) or Barbara Biedrzycki, R.N.
(biedrba@jhmi.edu) for more
information on eligibility criteria.
JAMA 286(8):921-929, 2001
Markers of Cancer Invasion
There is a great effort underway to identify new ways to identify cancers
that otherwise would remain undetected for too long. A major approach is
to identify tumor-specific markers and tissue-specific markers. For
example, useful markers could be proteins found reproducibly to be
produced by cancer cells in both tissue culture (cancer cells grown
artificially outside the body) and in patient samples. But there is
another potential type of marker, one that is produced by the invasive
tumor or the body's reaction to it. Such markers would not be normally
found in tissue culture and might not be present in normal tissues at a
high level. These are the invasion-specific markers.
July 9, 2001
Ryu, B., Jones, J., Hollingsworth, M. A., Hruban, R. H., and Kern, S. E.
Invasion-specific genes in malignancy: Serial analysis of gene expression
comparisons of primary and passaged cancers, Cancer Res. 61: 1833-1838,
2001.
(abstract)
Activin Receptors — A New Anticancer Signal in Human Tumors
The major problem with human tumors is a social one. Tumor cells do not
obey the signals from their surrounding cells that should restrain their
growth. To date, very few of such signals have been defined, and this
limits our ability to understand and counter this basic abnormality.
June
25, 2001
Reference
Su, G. H., Bansal, R., Montgomery, E., Yeo, C. J., Hruban, R. H., and
Kern, S. E. ACVR1B (ALK4) gene mutations in pancreatic carcinoma, Proc Natl Acad Sci USA. 98:
3254-3257, 2001.
Hopkins' Scientists use Molecular Tool to Discover New Markers of
Pancreatic Cancer
In the June 1st issue of Cancer Research (
http: //cancerres.aacrjournals.org/cgi/content/full/61/11/4320), Dr.
Argani and colleagues from Johns Hopkins described the discovery of a new
marker of pancreatic cancer. This new marker called "prostate stem-cell
antigen" (PSCA) was discovered by using a technique developed at Johns
Hopkins called "serial analysis of gene expression" (SAGE, see the
What's New May 28, 1997).
Since the original description of SAGE, a
group of cooperating scientists from a number of institutions have created
an online database of gene expression that includes SAGE data on a variety
of tissues and cancers (
http://www.ncbi.nlm.nih.gov/SAGE/ ). The investigators at Hopkins used
this database to compare the gene expression levels in pancreatic cancer
tissues with those seen in non-cancerous pancreatic tissues. The goal was
to identify genes that were selectively "turned-on" in the cancers. One of
the genes the Hopkins found using this approach coded for a protein called
"prostate stem-cell antigen." Prostate stem-cell antigen is a gene that
was originally thought to be largely restricted to prostate cells. Dr.
Argani and colleagues demonstrate that prostate stem-cell antigen (PSCA)
is, in fact, highly overexpressed in approximately 60% of primary
pancreatic cancers. It is not expressed in the normal pancreas.
June 7, 2001
Familial Pancreatic Cancer
For years, isolated reports in the medical literature have suggested that
pancreatic cancer runs in some families. For example, it has been reported
that former President Jimmy Carter lost his father, brother
and two sisters from pancreatic cancer.
March 23, 2001
Tersmette AC, Petersen GM, Offerhaus GJA, Falatko FC, Brune KA, Goggins M,
Rozenblum E, Wilentz RE, Yeo CJ, Cameron JL, Kern SE, and Hruban RH.
Increased risk of incident pancreatic cancer among first-degree relatives
of patients with familial pancreatic cancer. Clin Cancer Res 7:738-744,
2001.
New Vaccine to Treat Pancreatic Cancer
In the January issue of The Journal of Clinical Oncology
(volume 19; 2001: pages 145-156), Dr. Elizabeth Jaffee and colleagues
at Johns Hopkins report the result of a phase I clinical trial of a novel
vaccine treatment for patients with a pancreatic cancer. The vaccine was
produced by genetically altering pancreatic cancer cells growing in
culture so that the cells would produce large quantities of an immune
activating factor called "Granulocytic-macrophage colony-stimulating
factor" (or GM-CSF for short). Dr. Jaffee treated 14 patients with this
vaccine in a phase I dose escalation trial. The patients underwent surgery
at Hopkins after which they received various doses of the vaccine. No
dose-limiting toxicities were encountered. Instead, Dr. Jaffee was able to
demonstrate that the vaccine induced an anti-tumor immune response in
three patients who received the highest dose of the vaccine
(>10x107 vaccine cells). Remarkable, these three patients
remained alive and free of disease more than 25 months after diagnosis.
Based on these results, Dr. Jaffee and her team will be conducting phase
II trials of the GM-CSF vaccine. These trials are scheduled to begin in
the late spring - early summer.*
February 9, 2001