A mutant protein found in nearly all pancreatic cancers plays a role not only in the cancer’s development but in its continued growth, according to a new study from University of Michigan Comprehensive Cancer Center researchers. The finding suggests a possible target for developing new ways to treat this deadly disease.
Researchers have known that mutations in the Kras gene are what cause pancreatic cancer to develop. These mutations are frequently seen in common precancerous lesions, suggesting it has an early role in pancreatic cancer.
The new study, published in the February Journal of Clinical Investigation, finds that in mice, mutant Kras also keeps the tumor growing and helps precancerous tumors grow into invasive cancer. When the researchers turned off Kras, the tumors disappeared and showed no signs of recurring.
The researchers were able to manipulate Kras in a mouse model that they designed to look at Kras at various points in pancreatic cancer development. In the precancerous lesions, turning off Kras eliminated the tumors in mice and the pancreas tissue returned to normal, with no signs of the cancer returning. With invasive cancer, inactivating Kras killed off the cancer but left the pancreas with fibrous areas similar to scar tissue. Tumors did not recur.
Researchers hope this finding provides the basis for future drug development.
“Right now no drugs specifically target Kras, but there are drugs that target the cellular processes downstream of Kras. We next need to figure out which of these downstream effectors of Kras are important in pancreatic cancer,” says study author Marina Pasca di Magliano, Ph.D., assistant professor of surgery and of cell and developmental biology at the U-M Medical School.
Gene Involved In Pancreatic Cancer Identified
Researchers from the University of Michigan Comprehensive Cancer Center have identified a gene that is overexpressed in 90 percent of pancreatic cancers, the most deadly type of cancer.
Expression of the gene, Ataxia Telangiectasia Group D Complementing gene, called ATDC, is on average 20 times higher in pancreatic cancer cells than in cells from a normal pancreas. What’s more, the gene appears to make pancreatic cancer cells resistant to current therapies.
“One of the challenges in pancreatic cancer is that it is biologically aggressive and it does not respond well to chemotherapy or radiation. We found that ATDC not only causes the cancer cells to grow faster and be more aggressive, but it also makes the cancer cells particularly resistant to chemotherapy and radiation. By targeting this gene, we may be able to make cancer cells more sensitive to the therapies we already have in hand,” says senior study author Diane Simeone, M.D., director of the Multidisciplinary Pancreatic Cancer Clinic at the U-M Comprehensive Cancer Center.
Results of the study appear in the March issue of Cancer Cell.
Kras is also known to play a role in lung and colon cancer. But it is likely the biggest player in pancreatic cancer, where more than 90 percent of all tumors have mutated Kras. Pancreatic cancer is one of the most deadly types of cancer: about 4 percent of patients are alive five years after their diagnosis. The disease is often diagnosed when surgery is not an option and it tends to be resistant to available chemotherapies.
“There is a dire need for new therapies for pancreas cancer based on a better understanding of the biology of this disease. My lab is now looking at the downstream inhibitors of Kras to try to find the best target,” Pasca di Magliano says.
Genetic factors contribute significantly to the development of pancreatic cancer
In very rare cases, pancreatic cancer is caused by mutations in certain genes, such as BRCA2 (the familal breast cancer gene) and the CDKN2A (also known as p16, a tumor suppressor gene). Individuals with rare inherited conditions such as Hereditary Non-polyposis Colorectal Cancer (HNPCC), familial pancreatitis, and Peutz-Jeghers syndrome also have an increased risk of developing pancreatic cancer. However, this group represents only a small proportion of all those at risk of developing pancreatic cancer.
Recently, researchers have identified four more common genetic variants associated with increased risk of pancreatic cancer; which are located on chromosomes 1q32.1, 5p15.33, 9q34 and 13q22.1. The variant on chromosome 9 is located within the ABO gene that determines peoples’ ABO Blood Types.
Note to patients: This research was based in mice and needs further testing before any possible treatments are available for clinical trials. For information about current pancreatic cancer treatments, call the U-M Cancer AnswerLine at 800-865-1125.
Pancreatic cancer statistics: 43,140 Americans will be diagnosed with pancreatic cancer this year and 36,800 will die from the disease, according to the American Cancer Society
Additional authors: Meredith A. Collins, Filip Bednar, Yaqing Zhang, Jean-christophe Brisset, Stefanie Galban, Craig J. Galban, Sabita Rakshit, and Karen S. Flannagan, all from U-M; and N. Volkan Adsay from Emory University
Funding: U-M Biological Scholar Program; National Cancer Institute; U-M Gastrointestinal Specialized Program of Research Excellence (SPORE); Pancreatic Cancer Action Network; American Association for Cancer Research; Michigan Gastrointestinal Peptide Research Center
Source: University of Michigan Health System