New research finds that using a drug to "soften" tumors before chemotherapy doubles survival and reduces cancer spread in mouse models of pancreatic cancer - a disease with a low survival rate and few treatments for inoperable tumors.
The study - led by a team from the Garvan Institute of Medical Research in Sydney, Australia - is published in the journal Science Translational Medicine.
Dr. Marina Pajic and Dr. Paul Timpson, both of Garvan's Kinghorn Cancer Centre, co-led the research. Dr. Timpson says that the vision of the Pancreatic Cancer Action Network - to double pancreatic cancer survival by 2020 - inspired pancreatic cancer researchers from around the world to come together and work on the study.
Pancreatic cancer starts in the cells of the pancreas - a narrow, six-inch-long fish-shaped organ that sits behind the stomach.
The pancreas contains two main types of cell: exocrine cells that make enzymes for digestion, and endocrine cells that make hormones such as insulin and glucagon for controlling blood sugar. The vast majority of pancreatic cancers start in exocrine cells.
Unfortunately, as the early symptoms are vague and difficult to pin down, pancreatic cancer is often only diagnosed once it is advanced, leaving patients with inoperable tumors and few treatment options.
The dismal survival rate of just 7 percent has not altered much in 40 years, note the study authors.
Estimates from the American Cancer Society suggest that, in the United States, around 53,670 people will be diagnosed with pancreatic cancer and 43,090 people will die of the disease in 2017.
Priming the tumor overcomes treatment complication
Treatment options for inoperable pancreatic cancer are very limited - the standard-of-care is combination chemotherapy, but this only moderately improves survival.
- In the U.S., pancreatic cancer accounts for around 3 percent of all cancers and 7 percent of all cancer deaths.
- The average lifetime risk for both men and women is approximately 1 in 65 (or 1.5 percent).
- Smoking and being overweight are important risk factors for pancreatic cancer.
Treatment is further complicated by the fact that pancreatic tumors have a dense tissue structure that is difficult for drugs to penetrate.
For their study, the researchers used mice genetically engineered to develop pancreatic cancer, as well as mice implanted with patient-derived pancreatic tumor tissue.
They found that "priming" the tumors with a 3-day course of Fasudil before standard-of-care chemotherapy for pancreatic cancer doubled survival and reduced cancer spread.
Fasudil inhibits a protein called ROCK, which scientists believe stiffens cells surrounding tumors and helps to drive cancer progression. The drug is already in clinical use in Japan for the treatment of stroke, note the researchers.
They say that the drug temporarily "softens" the tumor tissue so that it more readily responds to the combination chemotherapy at both primary and secondary sites. It acts on the stroma - the complex microenvironment of cells, blood vessels, and other structures that surround the cancer cells.
The researchers say that the drug "slackens" the structure of this tumor microenvironment and also makes the blood vessels leaky. Both of these effects improve the effectiveness of the subsequent chemotherapy.
Stroma changes observed in real time
The team observed the effects in real time: using state-of-the-art intravital microscopy, they could see into the pancreatic tumors in the live mice. Dr. Pajic explains:
"We saw the stroma weaken over time, and [we] could also see that cancer cells did not spread so readily to secondary sites such as the liver."
With the help of quantum dots in the animals' bloodstream, the team was also able to watch how the blood vessels supplying the tumor changed over time.
"It was remarkable to watch the quantum dots radiate out from blood vessels adjacent to the tumors after Fasudil treatment - which is an indicator that the vessels have become leaky," says Dr. Pajic.
The interaction between cancer cells and the tumor microenvironment is known to be an important factor in tumor survival and progression of pancreatic cancer and other cancers that have solid tumors.
For example, researchers working on immunotherapy for cancers with solid tumors are also coming to the conclusion that tackling the tumor microenvironment is key to treatment success. This was recently highlighted in a study of immunotherapy for ovarian cancer.
"There has been a heated and longstanding controversy in cancer research about whether targeting the stroma can make pancreatic tumors more susceptible to therapy.
I think we have resolved that debate. We've been able to show for the first time that it's crucial to treat the stroma first and the tumor second, and to fine-tune the treatment timing to maximize outcome, while minimizing side effects."
Dr. Paul Timpson