LA JOLLA (June 22, 2026)—Pancreatic 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.
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.
The study was published in Proceedings of the National Academy of Sciences on June 22, 2026, and was funded by both federal research grants from the National Institutes of Health and private philanthropy.
"HDAC inhibitors have shown promise as cancer therapies, but they have not worked as well as researchers had hoped, in part due to toxicity issues," says co-corresponding author of the study Ronald Evans, PhD , professor and the March of Dimes Chair in Molecular and Developmental Biology at Salk. "Scientists have not fully understood how these drugs work in different cancers or how to use them more effectively. We set out to change that."
What do HDAC inhibitors do in pancreatic cancer?
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—but for foundational scientists, "complicated" isn't a reason to give up.
"When a drug doesn't live up to expectations in the clinic, people tend to walk away; but it's our job as basic researchers to understand why things don't work as expected rather than throwing out millions or billions of dollars of research," says co-corresponding author Michael Downes, senior staff scientist in Evans's lab. "By studying the underlying biology, we can often find better ways to use a drug, unlocking its full potential."
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.
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.
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.
"The activity of DNA damage repair genes is one reason why chemotherapy and other DNA-damaging therapies often have limited effectiveness," says first author Gaoyang Liang, a staff scientist in Evans's lab. "By combining entinostat with DNA-damaging therapies, we were able to make these treatments significantly more effective in pancreatic cancer models."
How do HDACs regulate DNA repair genes?
HDACs are traditionally known for helping keep genes turned off. They do this by limiting the access of DNA to the cell's 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's transcriptional machinery.
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.
"Think of HDACs as operations managers that help direct the cancer cells' resources towards critical functions like DNA repair," says Liang. "When we blocked HDAC activity, the cells lost that direction and could not keep DNA repair genes active anymore, making them vulnerable to DNA damage."
Making HDAC inhibitors more tolerable
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.
"People looked at HDAC inhibitors like entinostat—it has meaningful anti-tumor effects, but it can also cause toxicities," says co-author Morgan Truitt, PhD, a staff scientist in Evans's lab. "When you have a drug like that, it makes you wonder how you can make it work better clinically."
"One way is to lower the dose while exploiting something synergistically lethal with it," Truitt continues, "like 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."
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.
What's next?
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.
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.
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.
Other authors and funding
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; Hervé Tiriac and Andrew Lowy of UC San Diego; and Hadiqa Zafar and Jeremiah Johnson of MIT.
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.
About the Salk Institute for Biological Studies
The Salk Institute is an independent, nonprofit research institute founded in 1960 by Jonas Salk, developer of the first safe and effective polio vaccine. The Institute's mission is to drive foundational, collaborative, risk-taking research that addresses society's most pressing challenges, including cancer, Alzheimer's, and agricultural vulnerability. This foundational science underpins all translational efforts, generating insights that enable new medicines and innovations worldwide. Learn more at www.salk.edu .
