In two trials targeting some of the most challenging traits of pancreatic tumor cell growth, researchers from Dartmouth Medical School (DMS) and the Norris Cotton Cancer Center (NCCC) at Dartmouth-Hitchcock Medical Center (DHMC) have demonstrated success in slowing and preventing tumor development.
The NCCC research team was led by Dr. Murray Korc, a pioneer in early research on growth factor receptors in pancreatic cancer, and chair of the department of medicine at DMS and DHMC. An endocrinologist and cancer biologist, he focuses much of his research on the mechanisms that make pancreatic cancer so resilient and aggressive. Work reported in the May 15 issues of Clinical Cancer Research and Cancer Research addresses the team's latest advances.
Pancreatic cancer is characteristic for its ability to spread quickly, while becoming increasingly resistant to traditional chemotherapy. Generally diagnosed in an advanced state, it is frequently inoperable. As a result, it is the fourth leading cause of cancer death in adults in the US, killing more than 30,000 Americans every year, says Korc.
"By the time the disease is diagnosed, pancreatic cancer cells have a huge growth advantage over normal cells, which enables them to grow and metastasize very quickly," said Korc. "Our research has focused on determining what factors enable the cells to grow at such a fast rate and then how to slow that rate down and actually suppress pancreatic tumor growth."
Korc likens the disease to speeding in a car with an accelerator that is stuck to the floor. "Naturally, you apply the brakes but they don't work, so you begin pumping the brakes to slow the car down. The brakes are broken in pancreatic cancer but in addition, we found that the brake has been converted into an accelerator by the cancer cells. In essence, pumping the brakes gives you two accelerators."
In fact, said Korc, the inhibitory factors that have been proven to slow down the growth of normal cells, can often backfire and increase the spread of tumors in the pancreas, or in other words, change the brake into an accelerator.
In a feature article appearing in the May 15 edition of Clinical Cancer Research, Korc and Dr. Mitsuharu Fukasawa, a research associate in the department of medicine at DMS, reported a new, highly effective anti-angiogenic approach for treating pancreatic cancer. They focused on the over-expression of a molecule that hampers chemotherapeutic efforts in pancreatic cancer. The molecule, VEGF, is responsible for angiogenesis, a process that stimulates blood vessel formation. In pancreatic cancer cells, there is a 90-fold higher level of VEGF than in normal cells, which enables the cancer cells to grow and metastasize quickly and efficiently.
In this study, the researchers injected a protein sponge, VEGF-Trap, into mice bearing pancreatic tumors derived from four different human pancreatic cancer cells. They predicted the sponge would absorb most of the angiogenetic VEGF molecules, thereby slowing the blood vessel proliferation and suppressing tumor growth.
"The protein sponge completely suppressed pancreatic tumor growth," said Korc. "In all the tumors tested, there was a marked decrease in blood vessel formation, which is very exciting." The next step, he acknowledged, is to introduce this technology in humans, where it is desperately needed.
In the second study, published in Cancer Research, Korc and his research team, headed by his post-doctoral fellow Nicole Boyer Arnold, describe a novel mechanism for chemoresistance in pancreatic cancer. In their investigation, the team identified the pathways responsible for giving the pancreatic cancer cells a growth advantage and making them resistant to chemotherapeutic drugs. They focused on two molecules, Smad7 and thioredoxin, which are found in high quantities in many pancreatic tumors.
These molecules make signaling pathways abnormal so that when a drug is introduced to suppress cancer cell growth, these molecules allow the cancer cells to resist the drugs and to continue to grow. This chemo-resistance is a hallmark of aggressive cancers such as pancreatic cancer. "Now that we know this pathway exists, it will allow us and other investigators to try to figure out ways to interfere with this pathway to design new therapies for pancreatic cancer," said Korc. In future research, the research team will also introduce a molecular sponge to absorb certain over-expressed molecules that promote the expression of Smad7 and thioredoxin, in order to determine if this renders the cancer cells more responsive to therapy.
Although these studies are early, Korc is hopeful they will develop into clinical trials in the future. "The mortality rate (of pancreatic cancer) virtually equals incidence," he said. "Of the 31,000 people in the US that get it this year, 30,300 will die from it, and most patients die within six months. That is why we are excited about this research and hope that it will lead to more advances in the treatment of pancreatic cancer."
The studies were funded by the National Cancer Institute through two United States Public Health Service Grants awarded to Korc, and by a postdoctoral fellowship to DMS/NCCC researcher Nicole Boyer Arnold from the George E. Hewitt Foundation for Medical Research.