{"id":57015,"date":"2026-06-25T08:00:57","date_gmt":"2026-06-25T15:00:57","guid":{"rendered":"https:\/\/www.salk.edu\/?post_type=disclosure&#038;p=57015"},"modified":"2026-06-25T10:59:11","modified_gmt":"2026-06-25T17:59:11","slug":"foundational-research-points-to-new-therapeutic-strategies-for-an-emerging-cancer-drug","status":"publish","type":"disclosure","link":"https:\/\/www.salk.edu\/es\/news-release\/foundational-research-points-to-new-therapeutic-strategies-for-an-emerging-cancer-drug\/","title":{"rendered":"Foundational research points to new therapeutic strategies for an emerging cancer drug"},"content":{"rendered":"<ul style=\"margin-bottom: 30px;\">\n<li style=\"list-style: none; padding-left: -20px !important; margin-left: -20px !important;\"><strong>Lo m\u00e1s destacado<\/strong><\/li>\n<li>Salk researchers investigated the impacts of entinostat, a drug that targets HDAC proteins, and found it inactivates DNA damage repair genes in pancreatic cancer cells<\/li>\n<li>The discovery led to new treatment strategies that pair entinostat with DNA-damaging therapies and the development of a nanoparticle-based delivery approach that limits toxicity by selectively delivering entinostat to tumors<\/li>\n<li>The findings could improve treatment outcomes and expand therapeutic options for pancreatic cancer, and similar strategies could be applied for treating other cancer types that resist DNA-damaging therapies<\/li>\n<\/ul>\n<p>LA JOLLA\u2014Pancreatic cancer is one of the deadliest cancers and is the third leading cause of cancer-related death in the United States. While scientists continue searching for new therapies, important advances can also come from understanding how existing drugs work. By uncovering the underlying biology, researchers can identify new ways to use existing drugs, improve their effectiveness, and overcome barriers that have limited their clinical impact.<\/p>\n<figure id=\"attachment_57017\"  class=\"wp-caption alignright\"><a href=\"https:\/\/www.salk.edu\/wp-content\/uploads\/2026\/06\/2606-pr-evans-authors.jpg\"><img loading=\"lazy\" decoding=\"async\" width=\"458\" height=\"288\" class=\"img-responsive wp-image-57017 size-col-md-5\" src=\"https:\/\/www.salk.edu\/wp-content\/uploads\/2026\/06\/2606-pr-evans-authors-458x288.jpg\" alt=\"Gaoyang Liang (left) and Ronald Evans (right) led a study that reveals how HDAC inhibitors help pancreatic tumors resist DNA damage and developed new therapeutic strategies based on HDAC inhibition.\" srcset=\"https:\/\/www.salk.edu\/wp-content\/uploads\/2026\/06\/2606-pr-evans-authors-458x288.jpg 458w, https:\/\/www.salk.edu\/wp-content\/uploads\/2026\/06\/2606-pr-evans-authors-300x188.jpg 300w, https:\/\/www.salk.edu\/wp-content\/uploads\/2026\/06\/2606-pr-evans-authors-1024x643.jpg 1024w, https:\/\/www.salk.edu\/wp-content\/uploads\/2026\/06\/2606-pr-evans-authors-768x482.jpg 768w, https:\/\/www.salk.edu\/wp-content\/uploads\/2026\/06\/2606-pr-evans-authors-18x12.jpg 18w, https:\/\/www.salk.edu\/wp-content\/uploads\/2026\/06\/2606-pr-evans-authors-147x92.jpg 147w, https:\/\/www.salk.edu\/wp-content\/uploads\/2026\/06\/2606-pr-evans-authors-585x367.jpg 585w, https:\/\/www.salk.edu\/wp-content\/uploads\/2026\/06\/2606-pr-evans-authors-553x347.jpg 553w, https:\/\/www.salk.edu\/wp-content\/uploads\/2026\/06\/2606-pr-evans-authors-750x471.jpg 750w, https:\/\/www.salk.edu\/wp-content\/uploads\/2026\/06\/2606-pr-evans-authors-767x482.jpg 767w, https:\/\/www.salk.edu\/wp-content\/uploads\/2026\/06\/2606-pr-evans-authors-945x593.jpg 945w, https:\/\/www.salk.edu\/wp-content\/uploads\/2026\/06\/2606-pr-evans-authors.jpg 1500w\" sizes=\"auto, (max-width: 458px) 100vw, 458px\" \/><\/a><figcaption class=\"wp-caption-text\">Gaoyang Liang (left) and Ronald Evans (right) led a study that reveals how HDAC inhibitors help pancreatic tumors resist DNA damage and developed new therapeutic strategies based on HDAC inhibition.<br \/><a href=\"https:\/\/www.salk.edu\/wp-content\/uploads\/2026\/06\/2606-pr-evans-authors.jpg\" target=\"_blank\" rel=\"noopener\">Haga clic aqu\u00ed<\/a> para obtener una imagen en alta resoluci\u00f3n.<br \/>Cr\u00e9dito: Instituto Salk<\/figcaption><\/figure>\n<p>Foundational research conducted at the Salk Institute allows for this sort of innovation. In a new study, Salk researchers examined the effects of entinostat, an existing investigational cancer drug that inhibits enzymes called histone deacetylases (HDACs). Their insights led them to design new ways to use entinostat against pancreatic cancer, including combining it with therapies that induce DNA damage and developing a nanoparticle-based delivery method that reduces side effects.<\/p>\n<p>El estudio se public\u00f3 en <a href=\"https:\/\/doi.org\/10.1073\/pnas.2536040123\" target=\"_blank\" rel=\"noopener\"><em>Actas de la Academia Nacional de Ciencias<\/em><\/a> on June 25, 2026, and was funded by both federal research grants from the National Institutes of Health and private philanthropy.<\/p>\n<p>\u201cHDAC inhibitors have shown promise as cancer therapies, but they have not worked as well as researchers had hoped, in part due to toxicity issues,\u201d says co-corresponding author of the study\u00a0<a href=\"https:\/\/www.salk.edu\/es\/scientist\/ronald-evans\/\" target=\"_blank\" rel=\"noopener\">Ronald Evans, doctor<\/a>, professor and the March of Dimes Chair in Molecular and Developmental Biology at Salk. \u201cScientists have not fully understood how these drugs work in different cancers or how to use them more effectively. We set out to change that.\u201d<\/p>\n<h2 style=\"font-size: 20px; margin-top: 40px;\"><strong>What do HDAC inhibitors do in pancreatic cancer? <\/strong><\/h2>\n<p>Scientists have long been interested in HDAC inhibitors, including entinostat, because of their anti-cancer potential. However, normal healthy cells have HDAC proteins, too, and those need to stay intact. This complicates treatment with HDAC inhibitors like entinostat\u2014but for foundational scientists, \u201ccomplicated\u201d isn\u2019t a reason to give up.<\/p>\n<p>\u201cWhen a drug doesn\u2019t live up to expectations in the clinic, people tend to walk away; but it\u2019s our job as basic researchers to understand why things don\u2019t work as expected rather than throwing out millions or billions of dollars of research,\u201d says co-corresponding author Michael Downes, senior staff scientist in Evans\u2019s lab. \u201cBy studying the underlying biology, we can often find better ways to use a drug, unlocking its full potential.\u201d<\/p>\n<p>To explore the underlying biology of HDAC inhibitors, the Salk team examined both human and mouse pancreatic cancer cells and analyzed how gene activity changed after treatment with entinostat. They found an unexpected role for HDACs in controlling a critical group of genes in pancreatic cancer cells: those responsible for repairing damaged DNA. HDACs help keep these genes active, allowing pancreatic tumors to effectively fix DNA damage and survive.<\/p>\n<p>When HDAC activity was blocked with entinostat, DNA repair genes were turned down. As a result, cancer cells became less capable of repairing DNA damage and more vulnerable to therapies that induce damage.<\/p>\n<p>Many commonly used treatments for pancreatic cancer, including chemotherapy and radiation, work by inflicting enough DNA damage to kill cancer cells. But cancer cells often keep their DNA repair genes highly active, allowing them to quickly repair their DNA and evade death.<\/p>\n<p>\u201cThe activity of DNA damage repair genes is one reason why chemotherapy and other DNA-damaging therapies often have limited effectiveness,\u201d says first author Gaoyang Liang, a staff scientist in Evans\u2019s lab. \u201cBy combining entinostat with DNA-damaging therapies, we were able to make these treatments significantly more effective in pancreatic cancer models.\u201d<\/p>\n<h2 style=\"font-size: 20px; margin-top: 40px;\"><strong>How do HDACs regulate DNA repair genes?<\/strong><\/h2>\n<p>HDACs are traditionally known for helping keep genes turned off. They do this by limiting the access of DNA to the cell\u2019s transcriptional machinery, the collection of proteins responsible for reading DNA and switching genes on. So, why do HDACs play the opposite role for DNA repair genes? To find out, the researchers mapped HDAC activity across the cancer cell genome and examined how that affects the cell\u2019s transcriptional machinery.<\/p>\n<p>What they found pointed to a previously underrecognized role for HDACs. Rather than simply limiting DNA access, HDACs also help control the proper distribution of the transcriptional machinery across the genome. When HDAC activity was blocked, the transcriptional machinery was redistributed away from DNA repair genes, causing those genes to turn off.<\/p>\n<p>\u201cThink of HDACs as operations managers that help direct the cancer cells\u2019 resources towards critical functions like DNA repair,&#8221; says Liang. \u201cWhen we blocked HDAC activity, the cells lost that direction and could not keep DNA repair genes active anymore, making them vulnerable to DNA damage.\u201d<\/p>\n<h2 style=\"font-size: 20px; margin-top: 40px;\"><strong>Making HDAC inhibitors more tolerable<\/strong><\/h2>\n<p>With new insights into how HDAC inhibitors work in pancreatic tumors, the researchers next focused on improving their use in patients. Despite their anti-tumor potential, the use of HDAC inhibitors has been limited by toxic side effects that result from blocking HDAC activity in healthy tissues.<\/p>\n<p>\u201cPeople looked at HDAC inhibitors like entinostat\u2014it has meaningful anti-tumor effects, but it can also cause toxicities,\u201d says co-author Morgan Truitt, PhD, a staff scientist in Evans\u2019s lab. \u201cWhen you have a drug like that, it makes you wonder how you can make it work better clinically.\u201d<\/p>\n<p>\u201cOne way is to lower the dose while exploiting something synergistically lethal with it,\u201d Truitt continues, \u201clike combining entinostat with DNA-damaging agents. Another would be to maintain the effective drug dose and its anti-tumor effects while reducing toxicity to normal tissues. That is what led us to explore a nanoparticle-based delivery approach.\u201d<\/p>\n<figure id=\"attachment_57019\"  class=\"wp-caption aligncenter\"><a href=\"https:\/\/www.salk.edu\/wp-content\/uploads\/2026\/06\/2606-pr-evans-microscopy.jpg\"><img loading=\"lazy\" decoding=\"async\" width=\"1024\" height=\"502\" class=\"img-responsive wp-image-57019 size-large\" src=\"https:\/\/www.salk.edu\/wp-content\/uploads\/2026\/06\/2606-pr-evans-microscopy-1024x502.jpg\" alt=\"Mouse pancreatic tumors without treatment (left) and after treatment with entinostat bottlebrush nanoparticles (right), which cause elevated DNA damage (brown).\" srcset=\"https:\/\/www.salk.edu\/wp-content\/uploads\/2026\/06\/2606-pr-evans-microscopy-1024x502.jpg 1024w, https:\/\/www.salk.edu\/wp-content\/uploads\/2026\/06\/2606-pr-evans-microscopy-300x147.jpg 300w, https:\/\/www.salk.edu\/wp-content\/uploads\/2026\/06\/2606-pr-evans-microscopy-768x377.jpg 768w, https:\/\/www.salk.edu\/wp-content\/uploads\/2026\/06\/2606-pr-evans-microscopy-18x9.jpg 18w, https:\/\/www.salk.edu\/wp-content\/uploads\/2026\/06\/2606-pr-evans-microscopy-147x72.jpg 147w, https:\/\/www.salk.edu\/wp-content\/uploads\/2026\/06\/2606-pr-evans-microscopy-458x225.jpg 458w, https:\/\/www.salk.edu\/wp-content\/uploads\/2026\/06\/2606-pr-evans-microscopy-585x287.jpg 585w, https:\/\/www.salk.edu\/wp-content\/uploads\/2026\/06\/2606-pr-evans-microscopy-553x271.jpg 553w, https:\/\/www.salk.edu\/wp-content\/uploads\/2026\/06\/2606-pr-evans-microscopy-750x368.jpg 750w, https:\/\/www.salk.edu\/wp-content\/uploads\/2026\/06\/2606-pr-evans-microscopy-767x376.jpg 767w, https:\/\/www.salk.edu\/wp-content\/uploads\/2026\/06\/2606-pr-evans-microscopy-945x464.jpg 945w, https:\/\/www.salk.edu\/wp-content\/uploads\/2026\/06\/2606-pr-evans-microscopy.jpg 1500w\" sizes=\"auto, (max-width: 1024px) 100vw, 1024px\" \/><\/a><figcaption class=\"wp-caption-text\">Mouse pancreatic tumors without treatment (left) and after treatment with entinostat bottlebrush nanoparticles (right), which cause elevated DNA damage (brown).<br \/><a href=\"https:\/\/www.salk.edu\/wp-content\/uploads\/2026\/06\/2606-pr-evans-microscopy.jpg\" target=\"_blank\" rel=\"noopener\">Haga clic aqu\u00ed<\/a> para obtener una imagen en alta resoluci\u00f3n.<br \/>Cr\u00e9dito: Instituto Salk<\/figcaption><\/figure>\n<p>Working with collaborators at MIT, the researchers developed a version of entinostat loaded into bottlebrush-shaped nanoparticles. These nanoparticles preferentially accumulate in tumors and gradually release entinostat over time. In preclinical models, the nanoparticle-based therapy produced strong anti-tumor activity while reducing toxicity, suggesting it has a promising future for clinical translation.<\/p>\n<h2 style=\"font-size: 20px; margin-top: 40px;\"><strong>What\u2019s next?<\/strong><\/h2>\n<p>The researchers believe the findings will extend beyond pancreatic cancer. Many cancers rely on robust DNA repair to survive treatment, raising the possibility that HDAC inhibitors may enhance the efficacy of DNA-damaging therapies in other cancer types as well.<\/p>\n<p>Further optimization of the bottlebrush nanoparticles is also needed, including fine-tuning drug release rates to maximize their effect and loading them with both entinostat and a DNA-damaging agent so that both drugs are delivered to the same site at the same time.<\/p>\n<p>More broadly, the study highlights the ongoing need for fundamental research into how existing therapies work, so we can continue to discover new opportunities for their use and improve patient outcomes.<\/p>\n<h2 style=\"font-size: 20px; margin-top: 40px;\"><strong>Otros autores y financiaci\u00f3n<\/strong><\/h2>\n<p>Other authors include Jonathan Zhu, Daniel Cao, Gabriela Estepa, Dylan Nelson, Yang Dai, Tae Gyu Oh, Christopher Liddle, Ruth Yu, Tony Hunter, Dannielle Engle, Reuben Shaw, Weiwei Fan, and Annette Atkins of Salk; Hung Nguyen of MIT and Dartmouth College; Herv\u00e9 Tiriac and Andrew Lowy of UC San Diego; and Hadiqa Zafar and Jeremiah Johnson of MIT.<\/p>\n<p>The work was supported by the Lustgarten Foundation (122215393), Don and Lorraine Freeberg Foundation, David C. Copley Foundation, Wasily Family Foundation, Paul M. Angell Family Foundation, NOMIS Foundation, National Institutes of Health (CA220468, CA014195, CA265762, F32CA217033, P30 014195, P30 AG068635), Henry L. Guenther Foundation, and Waitt Foundation.<\/p>","protected":false},"featured_media":57021,"template":"","faculty":[91],"disease-research":[46,172],"class_list":["post-57015","disclosure","type-disclosure","status-publish","has-post-thumbnail","hentry","faculty-ronald-evans","disease-research-cancer-biology","disease-research-pancreatic-cancer"],"acf":[],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v27.6 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>Foundational research points to new therapeutic strategies for an emerging cancer drug - 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\/es\/news-release\/foundational-research-points-to-new-therapeutic-strategies-for-an-emerging-cancer-drug\/\" \/>\n<meta property=\"og:locale\" content=\"es_MX\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Foundational research points to new therapeutic strategies for an emerging cancer drug - Salk Institute for Biological Studies\" \/>\n<meta property=\"og:description\" content=\"Highlights Salk researchers investigated the impacts of entinostat, a drug that targets HDAC proteins, and found it inactivates DNA damage repair genes in pancreatic cancer cells The discovery led to new treatment strategies that pair entinostat with DNA-damaging therapies and the development of a nanoparticle-based delivery approach that limits toxicity by selectively delivering entinostat to tumors The findings could improve treatment outcomes and expand therapeutic options for pancreatic cancer, and similar strategies could be applied for treating other cancer types that resist DNA-damaging therapies LA JOLLA\u2014Pancreatic cancer is one of the deadliest cancers and is the third leading cause of cancer-related death in the United States. 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While scientists continue searching for new therapies, important advances can also come from understanding how existing drugs work. 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