A critical mass
Under the leadership of Mayer and DFCI molecular biologist Ronald DePinho, MD, and others, researchers in the Dana-Farber/Harvard Cancer Center have formed a powerhouse collaboration in gastrointestinal cancer research that includes a strong focus on the biology and genetics of pancreatic cancer. "There is a critical mass of investigators in pancreatic cancer here that exceeds any in the world," says DePinho. "There are 24 labs in the Harvard system that have a prominent or reasonable interest in this disease."
An organ located behind the stomach, the pancreas plays a key role in the digestive system.
DePinho and others in his laboratory, where a long-sought-after mouse model of this genetically complex cancer was developed in 2003, are sifting through pancreatic tumor samples, seeking altered genes that cause the disease and those needed to maintain its aggressive growth. They've already incriminated a handful of genetic changes that are candidates for testing with drugs tailored to block their cancer-causing behavior.
Like all cancers, pancreatic tumors develop from genetic mistakes — mutations, extra copies of genes, genes that have been lost from cells. DePinho, working with Lynda Chin, MD, and other colleagues, have been taking a top-down approach, using genomics tools to search the entire set of 46 chromosomes in a pancreatic cancer cell to look for abnormal alterations.
So far, the scientists have found at least 64 "massive rearrangements of the genome" and another 100 chromosomal regions with lesser changes, says Aram Hezel, MD, a medical oncology fellow in the DePinho lab who works on the project, along with graduate student Andrew Aguirre. In some part of the genome, the researchers have noted genetic material is damaged or missing, while in others it has been "amplified" — copied and recopied, like a photocopy machine running out of control. "Amplified regions are likely to be important to the tumor's existence," says Hezel, "and it's easier to produce a therapy against something that's in excess than against something that's missing."
Some of this genetic damage is simply bad luck, but the risks of pancreatic cancer rise with age and a history of smoking and chronic pancreatitis. Charles Fuchs, MD, a DFCI medical oncologist, heads an ongoing analysis of pancreatic cancer risk factors in some 320,000 people whose health has been monitored for decades in a group of trials, including the Nurses' Health Study. These studies have linked type 2 diabetes to a stronger risk of pancreatic cancer. Fuchs has gone a step further, showing that the same factors that lead to diabetes — obesity and lack of physical activity — independently raise the risk of pancreatic cancer.
Sapna Syngal, MD, MPH, reviews family cancer patterns with Michael Carlin, who is being treated for pancreatic cancer.
"Maintaining a healthy weight, exercising three times a week, and eating a diet with 'low glycemic load' — that is, avoiding foods like carbohydrates that raise blood sugar and insulin levels — can reduce your risk," he notes.
Only about 10 percent of pancreatic cancers are inherited, but in those cases it can devastate entire families. Former President Jimmy Carter, for example, has lost his three siblings and his father to the illness, but he remains cancer-free at age 80 and experts say he probably doesn't carry a susceptibility gene.
Scientists see in these tragedies a potential vein of gold: If they can identify inherited pancreatic cancer susceptibility genes, it could lead to genetic testing for healthy individuals and may shed light on the much more common non-familial cases.
"My father and five of his six siblings and his mother had cancers, including colon and pancreatic cancer," says Michael Carlin, 62, of Newton, Mass., who developed jaundice and was diagnosed with cancer of the pancreas in January 2004. Carlin, who had the Whipple operation, has contributed blood and tissue samples to Dana-Farber's Pancreatic Cancer Genes Study (PAGES), a registry set up roughly two years ago to aid the search for familial genes.
"We are adding three or four patients every week," says Sapna Syngal, MD, MPH, a specialist in gastrointestinal cancers at Dana-Farber and Brigham and Women's Hospital, who heads the PAGES effort, part of a nationwide registry led by the Mayo Clinic.
Although Carlin's DNA test revealed no known pancreatic cancer genes, Syngal told him she suspects his family's cancer-prone history is due to an undetected mutation that raises the risk for cancers of the colon, pancreas, ovary, and uterus. As a precaution, she recommends early and more frequent screening for his relatives.
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