Pancreatic cancer is one of the deadliest cancers – only one in eight patients survive five years after diagnosis. These dismal statistics are due in part to the thick, nearly impenetrable wall of fibrosis, or scar tissue, that surrounds most pancreatic tumors and makes it difficult for drugs to reach and destroy cancer cells.
Now, researchers at the Salk Institute have discovered how a class of cancer drugs called HDAC inhibitors can help treat pancreatic cancer by regulating the activation of fibroblasts—the cells that make up this scar tissue wall.
The new research was published in Nature communications on December 6, 2023.
“These drugs turn out to hit both the tumor itself and the fibrous tissue around it. This could be a very effective way to treat pancreatic cancers, which have usually been very difficult to reach,” says senior author Professor Ronald Evans. director of Salk’s Gene Expression Laboratory and March of Dimes Chair in Molecular and Developmental Biology.
In response to a new pancreatic tumor, the pancreas typically activates fibroblasts—the connective cells that support the structure of most organs. When converted from a resting state to an active state, fibroblasts create a thick layer of scar tissue around the cancer. While this normal protective mechanism can help ward off a cancer and prevent it from spreading, fibroblasts also produce signaling molecules that the tumor itself exploits to grow.
In the context of most pancreatic cancers, fibroblasts act as both good and bad players. It’s a double-edged sword.”
Michael Downes, senior staff scientist and co-corresponding author on the paper
In the new research, the team investigated the effect on fibroblasts of an experimental class of anticancer drugs known as histone deacetylase (HDAC) inhibitors. HDACs alter the three-dimensional structure of DNA inside cells, making certain sections of DNA easier or harder for other molecules to access and read. Targeting HDACs can therefore prevent cells from making major changes in their behavior, such as out-of-control cancer cell growth. But how the drugs work in all cell types is not well understood.
In experiments on isolated cells, the researchers found that HDAC inhibitors prevented fibroblasts from activating and supporting the tumor.
“Using HDAC inhibitors actually did two things: both reduced growth signals from fibroblasts to cancer cells and reduced the actual activation and accumulation of fibroblasts,” says Gaoyang Liang, first author and researcher in Evans’ lab. .
In mice, the researchers found that an experimental HDAC inhibitor, entinostat, reduced the activation of fibroblasts around pancreatic tumors and slowed tumor growth. When the researchers analyzed data from people with pancreatic cancer, they found something similar: the higher the levels of HDAC1 in the fibrous tissue around a patient’s tumor, the worse their outcome.
“This is consistent with what we saw in cells and mice,” says Downes. “If you have more HDAC activity in fibroblasts, you have a worse outcome. On the other hand, if you inhibit HDACs, you have a better outcome.”
Since HDAC inhibitors work by preventing cells from turning on certain genetic programs, the researchers wanted to know which sections of DNA affected by the drugs were most important for fibroblast activation. They identified several genes that block the expression of HDAC inhibitors—suggesting that new drugs could target these genes to block fibroblast activation and promote cancer growth and fibrosis.
“There have been some questions in the past about whether targeting fibroblasts is good or bad in pancreatic cancers, because people have shown that if you get rid of fibroblasts completely, it actually makes the cancers more aggressive,” says Annette Atkins. co-author of the study and a senior researcher in Evans’ lab. “But what our results show is that we don’t need to get rid of them; just limiting their activation is beneficial.”
More work is needed to identify the best way to deliver HDAC inhibitors to the dense fibrous tissue around pancreatic tumors, and how they might be most effectively combined with other cancer treatments.
Other authors of the paper are Tae Gyu Oh, Nasun Hah, Yu Shi, Morgan L. Truitt, Corina E. Antal, Annette R. Atkins, Yuwenbin Li, Antonio FM Pinto, Dylan C. Nelson, Gabriela Estepa, Senada Bashi, Ester Banayo, Yang Dai, Ruth T. Yu, Tony Hunter, and Dannielle D. Engle of Salk. Hervé Tiriac of UC San Diego; Cory Fraser of HonorHealth Scottsdale; Serina Ng, Haiyong Han, and Daniel D. Von Hoff of the Institute for Translational Genomics Research. and Christopher Liddle of the University of Sydney.
The work was supported by grants from the Lustgarten Foundation (including award 552873), the Don and Lorraine Freeberg Foundation, Ipsen Bioscience, a Stand Up To Cancer-Cancer Research UK-Lustgarten Foundation Pancreatic Cancer Dream Team Research Grant (SU2C-AACR- DT- 20-16), a Ruth L. Kirschstein National Research Service Award (F32CA217033), a Life Sciences Research Foundation grant, the Damon Runyon Cancer Research Foundation (DRG-2244-16), the National Institutes of Health (CA082683, 5T32CA009370 ), and the William Isacoff Research Foundation.
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Journal Reference:
Liang, G., et al. (2023). Inhibition of class I stromal HDACs limits pancreatic cancer progression. Nature communications. doi.org/10.1038/s41467-023-42178-6.
