Many types of cancer develop resistance to chemotherapeutic drugs over time, but pancreatic cancer seems to be inherently resistant and emerges unscathed from chemotherapy and radiation that can eradicate other solid tumors.
“If you look at pancreatic cancer under a microscope, it’s a sea of scar tissue with nests of cancer cells,” says Simeone. The dense fibrotic tissue surrounding the tumor makes it harder for drugs and radiation to reach and treat the cancer cells and explains some of pancreatic cancer’s resistance to treatment.
But there’s something else about pancreatic cancer that makes it so deadly — an innate aggressiveness that comes from the genetic mutations that drive its development and growth.
“I look at the tumor as a miniature natural selection process,” explains Pasca di Magliano. “It accumulates mutations randomly, but if one clone of tumor can grow faster, it will take over. The tumor selects for the meanest cells — the ones that ignore all the signals saying you really shouldn’t divide anymore.”
Scientists like Pasca di Magliano who study the genetics of pancreatic cancer focus on KRAS, because a mutant form of this gene is present in 90 to 95 percent of all human pancreatic tumors. The cancer-causing KRAS mutant triggers chronic inflammation in the pancreas, according to Pasca di Magliano’s newest research. Instead of recruiting immune cells that promote healing, the gene recruits immune cells that inflame surrounding tissue and help the tumor to grow.
Although the KRAS mutation is extremely important, Pasca di Magliano points out that many people acquire this mutation as they age, but never develop pancreatic cancer. “You need to have the KRAS mutant and then something else has to happen,” she says. The “something else” could be a mutation in a major tumor suppressor gene called p53; abnormal expression of a gene called ATDC, an oncogene discovered in Simeone’s lab that is a critical trigger to promote invasiveness; or defects in a signaling pathway called Hedgehog. All of these genetic abnormalities are common in pancreatic cancer.
In fact, researchers have found that malignant pancreatic tumors have an average of 63 mutations, and the specific combination of mutations varies widely from patient to patient. So drugs that target just one mutation may not be the answer.
Simeone believes an important clue to eradicating pancreatic cancer could involve targeting a subset of cells called cancer stem cells, which recently have been found to be present in several types of cancer. In 2007, Simeone and other U-M researchers discovered pancreatic cancer stem cells in human tumors by looking for three specific proteins on the cell’s surface. She found that it took just 100 of these stem cells to trigger cancer in research mice, as opposed to thousands of regular tumor cells.
“All our data supports the concept that this cell population is a driver of pancreatic cancer and is particularly resistant to standard therapies,” Simeone says. “If we want to cure pancreatic cancer, this cell population needs to be accounted for.”
In recent research, Simeone discovered that all pancreatic cancer stem cells are not created equal. She found that cancer stem cells in some human tumors have a different surface protein called c-Met. In combination with another cancer stem cell marker called CD44, c-Met triggers a super-aggressive form of pancreatic cancer that grows and metastasizes rapidly.
Up to 30 percent of the cancer stem cells found in some patient tumors analyzed in Simeone’s research were positive for CD44 and c-Met and were “incredibly aggressive,” according to Simeone. “Tumors with lower populations of CD44 and c-Met were much less aggressive and don’t seem to metastasize in mice.” These cells may be key to defining a cancer stem cell “signature” in pancreatic cancer.
Limited treatment options
In 15 to 20 percent of patients diagnosed with pancreatic cancer, surgery is an option, because the tumor is still confined within the pancreas. But the procedure is complicated by the tumor’s tendency to surround major blood vessels and nearby organs in the abdomen. Removing the tumor without damaging a major artery or vein requires the highest levels of experience and skill and sometimes is simply impossible.
Giving patients chemotherapy and radiation prior to surgery can help shrink the tumor and make it easier to remove surgically. And if the tumor cannot be removed with surgery, chemoradiation is the only possible treatment option.
One of the drugs most often used to treat pancreatic cancer is gemcitabine. It’s called a radiation sensitizer because, in addition to directly killing tumor cells, it makes tumor cells more sensitive to radiation. Determining the most effective way to combine gemcitabine with radiation has been a major focus of clinical trials conducted by U-M oncologists. U-M clinical researchers also are testing the effectiveness of combining gemcitabine with another class of drugs called checkpoint inhibitors that interfere with cells’ ability to repair damaged DNA.
While surgery and chemotherapy are widely accepted as treatments for pancreatic cancer, the effectiveness of radiation therapy is more controversial, especially for patients after surgery. A clinical trial in Europe of patients who had chemoradiation therapy after surgical resection of their tumor found no benefit. But a trial in the United States found that patients lived longer if they received post-surgical chemoradiation. A new clinical trial involving pancreatic cancer patients from many medical centers in Europe and the U.S., including the U-M Health System, will attempt to answer the question more definitively.