Photo by Todd McNaught
Pancreatic cancer begins with such ambiguous symptoms and is so rapidly fatal after diagnosis that scientists have had limited ability to study how the disease acquires its deadly force or even to be sure how it starts. Typically, by the time doctors detect the disease, it is already too late for surgery. Among the 20 percent of patients for whom surgery is an option, only 1 percent will survive 10 years.
But a recent paper describing the first-ever strain of mice designed to develop pancreatic cancer has sparked new optimism among those in search of a cure. The animal disease so accurately mimics each step of the human cancer, researchers now believe they finally have a tool in hand to move the field forward. The scientist who led the discovery, Dr. Sunil Hingorani, has recently joined the Hutchinson Center's Clinical Research Division, where he will be among the first to begin translating findings in the mouse into effective ways to detect and treat the human disease.
Dr. Fred Appelbaum, director of the Clinical Research Division, described Hingorani as a dedicated, committed researcher whose work has the potential to help save more than 30,000 lives — and an immeasurable amount of suffering — in the United States each year.
"Most obviously, Sunil brings a great deal of experience and success in developing models for pancreatic cancer, qualities that we believe will lead to earlier diagnosis and better therapies," he said. "With his addition to the division, I believe the Center is well on its way to becoming one of the nation's leaders for pancreatic-cancer research."
Despite the current grim prognosis for pancreatic-cancer patients, Hingorani believes that new research opportunities can boost survival rates.
"Pancreatic cancer is unusually lethal," said Hingorani, also a member of the Public Health Sciences Division, where his laboratory is located. "It's essentially 100 percent fatal. But when we look closely at the outcomes of patients who were treated with surgery, we see some interesting data that tell us that we should be able improve survival rates through earlier detection of the disease."
Patients who are eligible for surgery because their disease appears not to have spread beyond the pancreas have a five-year survival rate that ranges from 15 percent to 40 percent. Yet, Hingorani said, their long-term survival is still close to zero. Doctors have been surprised to find that many of these surgical patients die from tumors in their lungs, liver or other organs — tumors that were undetectable at the time of surgery but that must have spread, or metastasized, from the pancreas.
"That suggests that from its very inception as an invasive disease, pancreatic cancer must already be developing micrometastases — small numbers of cancerous cells that have spread either locally or to distant organs," he said. "That means we'll need to find ways to detect the cancer extremely early in the course of the disease — at a pre-invasive state when the cells are abnormal but not yet fully cancerous."
Scientists have thus far only been able to speculate what this precancerous state might look like in humans. That challenged Hingorani to develop a mouse model that faithfully mimics human pancreatic cancer from its inception to its advanced stage, a project he initiated with colleague Dr. David Tuveson, while an instructor of medicine and cancer biology at the Abramson Cancer Research Institute at the University of Pennsylvania.
Dr. Teri Brentnall, an associate professor of medicine at the University of Washington, is among many in the field who appreciate the potential applications of Hingorani's mouse model. Brentnall leads a project to detect early stage pancreatic cancer in individuals with a family history of the disease. Her lab seeks to identify protein clues in the blood that signify early onset of the disease or that help doctors monitor a patient's response to therapy.
"We are extraordinarily lucky to have Sunil join our efforts in the battle against pancreatic cancer," she said. "His pancreatic-cancer mouse model very closely recapitulates the cancer seen in humans. The model is essential for validation of candidate protein markers as well as for studies of vaccine therapy and to investigate drugs that may prevent the disease."
Through a trick of genetic engineering, the mice can essentially be programmed to activate and/or deactivate one or several of the genes that have been found to be mutated in human pancreatic tumors. Depending on the timing and combination of defects that are programmed, the mice either develop cancer slowly or experience more aggressive forms of the disease.
Hingorani said one of the most interesting defects is in a gene called K-ras, which is mutated in about 90 percent of human pancreatic cancers.
"We found that if mice do not have this mutation, they never develop pancreatic cancer," he said. "That tells us that this mutation may represent the rate-limiting step for the disease to initiate."
The mice that harbor only K-ras mutations develop a precancerous condition that usually does not begin to invade surrounding tissue. Invasiveness is a hallmark of cancer. Yet as the mice age, some of them will spontaneously progress to cancer as they acquire defects in additional genes. The entire process appears very similar to what experts have hypothesized to occur in humans, Hingorani said.
Mice that develop full-blown pancreatic cancer also show identical symptoms to humans. "For example, they recapitulate many of the clinical signs such as lethargy, cachexia (wasting) and abdominal distension from the accumulation of ascites (fluid in the abdominal cavity). The cancer also spreads to the same organs as in humans and with nearly the same frequency."
For Hingorani, whose career combines laboratory research with clinical practice, the real value of this similarity is its potential to reveal key proteins in the blood that may alert doctors to the presence of early stage cancer — so called biomarkers — or that could serve as targets for new drugs to either prevent cancer or to treat it if it develops. Individuals with a family history of the disease — and therefore at high risk themselves — are an ideal population group in which to test the clinical potential of newly discovered markers or preventive drugs. He expects to collaborate on such studies with Brentnall, whose work was among the factors that drew him to Seattle.
Hingorani also hopes that the mice will serve as an important proving ground for generating data on experimental therapies before they are taken into the clinic. Pancreatic cancer is unusually resistant to radiation and virtually all chemotherapy drugs.
"The median survival after diagnosis of pancreatic cancer is four to six months," he said. "Should a patient be so lucky as to have the opportunity to enroll in a clinical trial, they will only have one shot at an experimental treatment. I believe that every drug should be given a chance in the clinic if there is sufficient scientific rationale to do so — and the mouse model could be very important for providing those data."
Earlier this year, Hingorani received an American Association for Cancer Research — Pancreatic Cancer Action Network Career Development Award.
Prior to joining the Abramson Cancer Center in 2002, where he collaborated on the mouse model with Dr. David Tuveson, Hingorani was a postdoctoral fellow at the Massachusetts Institute of Technology. He completed his residency at Brigham and Women's Hospital in Boston and a clinical fellowship in hematology and oncology at Dana Farber Cancer Institute/Brigham and Women's Hospital/Massachusetts General Hospital Cancer Care Program. He obtained a doctorate in cellular and molecular physiology and a medical degree from Yale University.
At the Hutchinson Center, Hingorani joins a growing group of investigators conducting so-called "translational research" on solid-tumor cancers in order to bring new therapies into the clinic.
"The Center has taught the world about advanced treatments for blood cancers," he said. "I'm excited to be a part of our efforts to extend that excellence to the treatment of solid tumors."