{"id":43385,"date":"2023-12-06T07:26:06","date_gmt":"2023-12-06T15:26:06","guid":{"rendered":"https:\/\/vermont.salk.edu\/?post_type=disclosure&p=43385"},"modified":"2024-01-30T13:48:06","modified_gmt":"2024-01-30T21:48:06","slug":"how-drugs-can-target-the-thick-scar-tissue-of-pancreatic-cancer","status":"publish","type":"disclosure","link":"https:\/\/www.salk.edu\/zh\/news-release\/how-drugs-can-target-the-thick-scar-tissue-of-pancreatic-cancer\/","title":{"rendered":"How drugs can target the thick \u201cscar tissue\u201d of pancreatic cancer"},"content":{"rendered":"

LA JOLLA\u2014Pancreatic cancer is one of the deadliest cancers\u2014only about one in eight patients<\/a> survives five years after diagnosis. Those dismal statistics are in part due to the thick, nearly impenetrable wall of fibrosis, or scar tissue, that surrounds most pancreatic tumors and makes it hard for drugs to access and destroy the cancer cells. <\/p>\n

Now, researchers at the Salk Institute have discovered how a class of anti-cancer drugs called HDAC inhibitors can help treat pancreatic cancer by modulating the activation of fibroblasts\u2014the cells that make up that wall of scar tissue. <\/p>\n

The new research was published in Nature Communications<\/a><\/em> on December 6, 2023. <\/p>\n

\"From<\/a>
From left: Yang Dai, Gabriela Estepa, Ruth Yu, Tony Hunter, Michael Downes, Annette Atkins, Yuwenbin Li, Gaoyang Liang, Dylan Nelson, and Ronald Evans.
Click here<\/a> for a high-resolution image.
Credit: Salk Institute<\/figcaption><\/figure>\n

\u201cThese drugs turn out to be hitting both the tumor itself as well as the fibrotic tissue around it. This could be a very effective way to treat pancreatic cancers, which have typically been very difficult to reach,\u201d says senior author Professor \u7f57\u7eb3\u5fb7\u00b7\u57c3\u6587\u65af<\/a>, director of Salk\u2019s Gene Expression Laboratory and March of Dimes Chair in Molecular and Developmental Biology.<\/p>\n

In response to a new pancreatic tumor, the pancreas typically activates fibroblasts\u2014the connective cells that support the structure of most organs. When flipped from a resting state to an active state, fibroblasts build a thick layer of scar tissue around the cancer. While this normal protective mechanism can help wall off a cancer and prevent its spread, fibroblasts also produce signaling molecules that the tumor itself takes advantage of to grow. <\/p>\n

\u201cIn the context of most pancreatic cancers, fibroblasts are acting as both good players and bad players,\u201d says Michael Downes, senior staff scientist and co-corresponding author on the paper. \u201cIt\u2019s a double-edged sword.\u201d<\/p>\n

In the new research, the team probed the effect on fibroblasts of an experimental class of cancer drugs known as histone deacetylase (HDAC) inhibitors. HDACs alter the three-dimensional structure of DNA inside cells, making some stretches of DNA easier or harder for other molecules to access and read. Targeting HDACs can therefore prevent cells from making large changes to their behavior, such as the out-of-control growth of cancer cells. But how the drugs work on all cell types is not well understood.<\/p>\n

\"The<\/a>
The abundance of cancer-associated fibroblasts (magenta) in the microenvironment with pancreatic cancer cells (green).
Click here<\/a> for a high-resolution image.
Credit: Salk Institute<\/figcaption><\/figure>\n

In experiments on isolated cells, the researchers discovered that HDAC inhibitors prevented fibroblasts from becoming activated and tumor supportive. <\/p>\n

\u201cUsing HDAC inhibitors actually did two things\u2014it both turned down the growth signals from the fibroblasts to the cancer cells and it reduced the actual activation and accumulation of the fibroblasts,\u201d says Gaoyang Liang, first author and research associate in Evans\u2019 lab.<\/p>\n

In mice, the researchers found that one experimental HDAC inhibitor, entinostat, both reduced the activation of fibroblasts around pancreatic tumors and slowed tumor growth. When the researchers analyzed data from humans with pancreatic cancer, they discovered something similar: the higher the levels of HDAC1 in the fibrotic tissue around a patient\u2019s tumor, the worse their outcome. <\/p>\n

\u201cThis is in agreement with what we saw in cells and in mice,\u201d says Downes. \u201cIf you have more HDAC activities in the fibroblasts, you have a worse outcome. On the other hand, if you inhibit the HDACs, you have a better outcome.\u201d<\/p>\n

Since HDAC inhibitors work by preventing cells from activating certain genetic programs, the researchers wanted to know which stretches of DNA impacted by the drugs were most relevant for fibroblast activation. They identified several genes that HDAC inhibitors prevent from being expressed\u2014suggesting that new drugs could target those genes to keep fibroblasts from becoming activated and promoting cancer growth and fibrosis.<\/p>\n

\u201cThere have been some questions in the past about whether targeting fibroblasts is a good thing or a bad thing in pancreatic cancers, because people have shown that if you get rid of fibroblasts altogether it actually makes the cancers more aggressive,\u201d says Annette Atkins, co-author of the study and senior research scientist in Evans\u2019 lab. \u201cBut what our results suggest is that we don\u2019t have to get rid of them; just limiting their activation is beneficial.\u201d<\/p>\n

More work is needed to pinpoint how to best deliver HDAC inhibitors to the dense fibrotic tissue around pancreatic tumors, as well as how they might be most effectively combined with other cancer treatments. <\/p>\n

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 F. M. Pinto, Dylan C. Nelson, Gabriela Estepa, Senada Bashi, Ester Banayo, Yang Dai, Ruth T. Yu, Tony Hunter, and Dannielle D. Engle of Salk; Herv\u00e9 Tiriac of UC San Diego; Cory Fraser of HonorHealth Scottsdale; Serina Ng, Haiyong Han, and Daniel D. Von Hoff of The Translational Genomic Research Institute; and Christopher Liddle of the University of Sydney.<\/p>\n

The work was supported by grants from the Lustgarten Foundation (552873, 122215393-02), Don and Lorraine Freeberg Foundation, the David C. Copley Foundation, the Wasily Family Foundation, Ipsen Bioscience, a Stand Up To Cancer-Cancer Research UK-Lustgarten Foundation Pancreatic Cancer Dream Team Research Grant (SU2C-AACR-DT-20-16), the NOMIS Foundation, a Ruth L. Kirschstein National Research Service Award (F32CA217033), a Life Sciences Research Foundation Fellowship, the Damon Runyon Cancer Research Foundation (DRG-2244-16), an Institutional Research Training Grant (5T32CA009370), the National Institutes of Health (CA220468, CA265762, CA082683, 5T32CA009370, NCI CCSG: P30 014195), the Waitt Foundation, and the William Isacoff Research Foundation.<\/p>","protected":false},"featured_media":44274,"template":"","faculty":[91],"disease-research":[46,333,172],"class_list":["post-43385","disclosure","type-disclosure","status-publish","has-post-thumbnail","hentry","faculty-ronald-evans","disease-research-cancer-biology","disease-research-genetics","disease-research-pancreatic-cancer"],"acf":[],"yoast_head":"\nHow drugs can target the thick \u201cscar tissue\u201d of pancreatic cancer - Salk Institute for Biological Studies<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.salk.edu\/zh\/news-release\/how-drugs-can-target-the-thick-scar-tissue-of-pancreatic-cancer\/\" \/>\n<meta property=\"og:locale\" content=\"zh_CN\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"How drugs can target the thick \u201cscar tissue\u201d of pancreatic cancer - Salk Institute for Biological Studies\" \/>\n<meta property=\"og:description\" content=\"LA JOLLA\u2014Pancreatic cancer is one of the deadliest cancers\u2014only about one in eight patients survives five years after diagnosis. 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