Journal of the National Cancer Institute Advance Access originally published online on September 25, 2007
JNCI Journal of the National Cancer Institute 2007 99(19):1432-1434; doi:10.1093/jnci/djm180
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© Oxford University Press 2007.
NEWS |
Pancreatic Cancer Research Matures
Pancreatic cancer research is a field fraught with opportunity. Early detection and effective treatments are the two biggest needs in a research area that has been slow to advance. But a closer look reveals that progress is being made on several fronts.
Researchers can now describe the progression of genetic lesions from precancer to full-blown disease. They have found candidate genes for diagnosis, screening, and treatment, many of which are being tested in trials. Several new risk factors have been identified. And a whole-genome scan of about 2,000 pancreatic cancer patients revealed new genetic targets and pathways affected by the disease.
Currently, most pancreatic cancer patients die within a year of diagnosis. By the time symptoms appear, 80% have already metastasized. The overall 5-year survival rate is about 5%, the lowest of all major cancers. Patients with localized disease who have their pancreas removed do a little better; their 5-year survival rate is about 25%. Today, it is the fourth-leading cause of cancer deaths in both men and women.
Treatment options are limited. Gemcitabine has been the standard of care for advanced pancreatic cancer for the past 10 years. Recently, gemcitabine together with erlotinib was approved by the U.S. Food and Drug Administration for treatment of advanced pancreatic cancer. The epidermal growth factor receptor, erlotinib's target, is overexpressed in many pancreatic tumors and is associated with poor prognosis. However, the combination extended overall survival of patients with advanced disease by an average of just about 10 days—from 5.91 months to 6.24 months—compared with gemcitabine alone.
It is not for lack of effort that effective treatments have been slow to advance. Both the National Cancer Institute and private foundations have supported research over the years. Even though several phase III trials of new agents combined with gemcitabine did not show any survival improvement, another 200 clinical trials are currently recruiting patients to test a wide range of agents.
"There is a tremendous need to find effective drugs, particularly for the majority of patients who present with metastatic, surgically inoperable disease," said Anirban Maitra, M.B.B.S., an associate professor of pathology and oncology at Johns Hopkins University School of Medicine in Baltimore. "None of the currently approved drugs has a dramatic impact on enhancing survival. Right now, the bar for drug approval for advanced pancreatic cancer is very low."
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Molecular Alterations
While the lack of response to therapy is a real problem, some progress has been made toward understanding the genetic changes in precancerous pancreatic lesions. Many researchers think that the most common precancerous lesions, PanINs (pancreatic intraepithelial neoplasias), proceed through various stages to invasive carcinoma, with each stage accumulating additional genetic abnormalities. During this process, certain tumor-suppressor genes are inactivated in many tumors. For example, the gene for the p16 protein, a critical regulator of the cell cycle, is inactivated in about 95% of pancreatic cancers. Likewise, the gene for the p53 protein, important in the cell cycle and apoptosis, is inactivated in 55%–75% of pancreatic cancers.
Several oncogenes are also commonly found in pancreatic tumors. KRAS, a molecular switch connecting cell surface receptors to target enzymes in the cell, is activated in more than 90% of pancreatic tumors before invasive cancer develops and only at a few specific places in the gene. Also, genes involved in detecting and repairing DNA damage—MLH1, MSH2, and BRCA2—are inactivated in a subset of pancreatic cancers. And pancreatic cancer cells consistently overexpress a protein called mesothelin, which is normally involved in cell–cell interactions, and have an abnormally active hedgehog signaling pathway, which is usually active in utero but turned off in most adult cells.
Drug Development
Several of these common molecular alterations have therapeutic and diagnostic implications. Testing for mutations in the KRAS gene, for example, may in theory be used as a screening tool for early pancreatic cancers. In fact, researchers were able to detect KRAS mutations in the pancreatic duct juice, collected during endoscopic imaging of patients, which they are now testing in a screening study. And pancreatic cancer patients with specific BRCA2 mutations may benefit from several agents, including mitomycin C, a cancer drug shown to be effective in cells with BRCA2 defects. Scott E. Kern, M.D., from the department of pathology at Johns Hopkins, is trying to identify which of the 400 FDA-approved cancer drugs are responsive to cells with a DNA-repair defect in BRCA2.
Likewise, drugs are being developed to inhibit the hedgehog signaling pathway, which is particularly active in many pancreatic cancers. One in particular, cyclopamine, currently under investigation for the treatment of several cancers, has been shown to have effect in pancreatic cancer mouse models, particularly on metastatic disease.
Some investigators are looking for new targets. James Abbruzzese, M.D., professor of medicine in the department of gastrointestinal medical oncology at the University of Texas M. D. Anderson Cancer Center in Houston, is interested in proteins involved in the formation of chromosomal instability pathways, which are common to several cancers. He is also working in fruit flies to find new mutant genes that along with p53 and KRAS mutations cause the flies to die. Donald J. Buchsbaum, Ph.D., principal investigator of the pancreatic SPORE (specialized programs of research excellence) program at the University of Alabama at Birmingham is working with TRAIL, a ligand that binds to cell death receptors and induces apoptosis. They have some promising data treating pancreatic cancer in mice with drugs aimed at that target, combined with chemotherapy.
Screening Efforts
Besides the search for effective treatments, researchers also want to find a screening tool to detect lesions early enough to prolong lives. A clinical study is under way, led by Marcia I. Canto, M.D., also of Johns Hopkins, that they hope will identify cancer early in high-risk people. The group is currently recruiting 200 symptomless people with a family history of pancreatic cancer or an increased risk because of known germline mutations in BRCA2, p16, or STK-11. Endoscopic ultrasonography, computed tomography, and magnetic resonance imaging will be used for screening in the study, called CAPS3 (Cancer of the Pancreas Screening Study). Those with suspicious precancerous lesions will be offered surgery.
In a smaller pilot study, Canto examined 78 people from the same high-risk populations with endoscopic ultrasonography and computed tomography scans and found that eight people, or 10%, had abnormal lesions, which were then confirmed by surgery or fine-needle aspiration.
Besides trying to find a screening tool for precancerous lesions, the CAPS3 trial is validating a panel of markers in pancreatic juice and blood that might be able to predict the presence of early lesions not visible by radiology. The trial will look for two proteins in the blood serum—CA19-9 and macrophage inhibitory cytokine 1—and alterations in pancreatic juice DNA, including KRAS mutations and methylation patterns of other genes.
Another search for blood proteins that predict early-stage disease is led by Anna E. Lokshin, Ph.D., an associate professor of medicine and pathology at the University of Pittsburgh. She identified a panel of 10 proteins that were able to discriminate between blood from 100 pancreatic patients versus 400 healthy controls. Ninety-five percent of cancer cases were correctly identified and 98% of noncancers. She is repeating the experiment with blood from 270 pancreatic cancer patients and 400 controls. To see if the blood markers can identify pancreatic cancer at an early treatable stage, she is going to test blood samples from 120 participants in the Prostate, Lung, Colorectal, and Ovarian (PLCO) screening trial who went on to develop pancreatic cancer.
Risk Factors
The final area that is advancing is identifying the risk factors for pancreatic cancer. "We're not in the same place we were 10–15 years ago, when smoking was the only known risk factor," said Debra Silverman, Sc.D., in the division of cancer genetics and epidemiology at NCI. While smoking explains about 25% of pancreatic cancer cases, family history of pancreatic cancer, chronic pancreatitis, longstanding diabetes, and elevated body mass index have emerged as risk factors, according to Silverman.
Progress in this area is due partly to the conduct of high-quality case–control studies based on direct interviews with patients, rather than their next of kin. It is due also to the fact that large cohort studies—like the American Cancer Society prevention study, the Nurses' Health Study, PLCO, and the NIH–American Association of Retired People study, which monitor healthy people for long periods—have begun to yield enough pancreatic cancer patients for study.
Future Directions
Many of these research groups are involved in another major research effort known as PanScan. This large pancreatic cancer cohort consortium was launched by NCI's epidemiology and genetic research program in the fall of 2006. PanScan consists of one case–control study and 12 large cohort studies, including the Women's Health Initiative, the American Cancer Society study, PLCO, and a large European cancer and nutrition study, all funded partially or totally by NCI. By pooling resources, the researchers hope to identify both the genetic and environmental risk factors for pancreatic cancer.
"The cohorts were started many years ago—some in the ’70s and ’80s, but most in the 1990s," explained Rachael Stolzenberg-Solomon, Ph.D., from NCI's division of cancer epidemiology and genetics. Blood samples and questionnaires about lifestyle and environmental exposures were collected at the beginning of the cohort when the study participants were all healthy.
Each consortium member has agreed to contribute DNA samples and questionnaire data from cohort participants before they developed pancreatic cancer. By pooling data, the total will be about 2,000 pancreatic cancer patients and 2,000 controls. "Just about all of them have sent their DNA to the NCI genotyping facility, where each whole-genome scan will analyze 550,000 single-nucleotide polymorphisms, the most common variants in the human genome," said Patricia Hartge, Sc.D., also from NCI.
While the data from the genome scans are collected and analyzed, data from the questionnaires on lifestyle and environmental exposures will be pooled and analyzed. The genetic findings and a separate analysis of the lifestyle and environmental exposures are expected to be published next spring. Eventually, a set of reports that look at gene–environment and gene–lifestyle interactions will follow.
Gene variants associated with pancreatic cancer may give clues about which molecular pathways are involved, as well as suggesting yet more therapeutic targets. "We're probably going to find the usual suspects that we've known about for a while but also a whole slew of additional genes that are associated with the risk for developing pancreatic cancer," Abbruzzese said. "We hope these will provide some novel insights into the pathways involved in the cancer cells and will suggest new pathways that we might target."
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