Pancreatic cancer is one of the toughest forms of the disease to treat, because it often causes no symptoms until it has spread beyond the pancreas. Now, a team led by the Garvan Institute of Medical Research in Australia has discovered one method by which pancreatic cancer cells spread and shield themselves from chemotherapy—a finding that could provide a new two-pronged approach to treating the disease, they said.
The researchers discovered that some pancreatic tumors overproduce perlecan, a type of protein that helps cancer cells change the “cellular matrix”—the tissue that holds tumors together. That remodeling of the tumor's environment allows cancer cells to travel to other parts of the body. The perlecan also seems to protect the cells from chemotherapy.
The team lowered levels of perlecan in mouse models of pancreatic cancer and observed a drop in the spread of the cancer and an improvement in the response to chemotherapy. They reported their findings in the journal Nature Communications.
The Garvan-led team started with samples of matrix tissue from both metastatic and nonmetastatic pancreatic tumors in mice. Then they extracted cells called fibrobasts, which produce much of the matrix, from both types of tumors and mixed them with the cancer cells. They discovered that when they added fibroblasts from metastatic pancreatic tumors to cancer cells from nonmetastatic tumors, the tumors that weren’t spreading before started to break out of the matrix and travel.
“Our results suggest that some pancreatic cancer cells can ‘educate’ the fibroblasts in and around the tumor,” said lead author Claire Vennin, Ph.D., now a postdoctoral research fellow at the Netherlands Cancer Institute, in a statement. “This lets the fibroblasts remodel the matrix and interact with other, less aggressive cancer cells in a way that supports the cancer cells' ability to spread.”
The finding, Vennin added, suggests a strategy of inhibiting the fibroblasts from aggressive pancreatic tumors first, then following up with chemotherapy.
A number of combination strategies are being pursued for treating pancreatic cancer, though there have been some notable failures of late. Last month, Boston Biomedical announced it halted a phase 3 trial of its experimental drug napabucasin alongside two chemotherapy drugs due to a lack of efficacy, for example.
GlaxoSmithKline is hoping its experimental RIP1 inhibitor will chart positive results in pancreatic cancer as part of a combination with Merck’s immuno-oncology blockbuster Keytruda. The company started a phase 1/2 trial late last year after showing that in mice, the combo treatment doubled the activation of so-called killer T cells—immune cells that target cancer cells. GSK is recruiting patients with pancreatic ductal adenocarcinoma for the trial.
The Garvan-led research team used gene editing to reduce levels of perlecan in mouse models and live-imaging tools to track individual cancer cells. That allowed them to watch in real time the slowdown in the spread of the cancer cells as well as the improvement in their response to chemotherapy.
Vennin and her colleagues believe it will be possible to identify genetic changes in pancreatic tumors that cause them to become aggressive, then to target fibroblasts in those patients with perlecan-reducing therapies. Such a strategy could potentially render them “more susceptible to our currently approved treatments, which would significantly change how we treat this aggressive cancer," she said.