Pancreatic cancer is notoriously aggressive and difficult to detect early. By the time it is diagnosed, it has often spread to other tissues, making it nearly untreatable. Central to the progression of pancreatic cancer are pancreatic stellate cells, which regulate the production of extracellular matrix. During tumor development, these cells activate and transform into fibroblasts that produce excess collagen, shielding the cancer cells with a fibrous scar that makes the tumor unreachable to most drugs (1).
Researchers from the Salk Institute for Biological Studies tested a new drug for its ability to inhibit the transformation of pancreatic stellate cells into tumor-promoting fibroblasts (2). “It looks like this reprogramming is bringing in a fibroblast population that is not pro-tumorigenic anymore, and it probably is tumor restraining to a certain extent,” said Raghu Kalluri, a cancer biologist at the MD Anderson Cancer Center who was not involved in the study. Published in Nature Communications, these findings underscore the potential of targeting both tumor growth and fibrosis to decelerate pancreatic cancer progression.
The Salk researchers, led by molecular endocrinologist Ronald Evans, had previously expressed the vitamin D receptor in pancreatic stellate cells and shown that vitamin D analogs reprogrammed activated pancreatic stellate cells, enhancing the efficacy of chemotherapy. This success raised the question of whether other epigenetic-based strategies might also be effective in cancer treatments.
We were able to reduce the proliferation of the tumor and open up the environment so drugs could come in more efficiently.
– Ronald Evans, Salk Institute for Biological Studies
Evans and his team turned to histone deacetylases (HDAC), enzymes that tighten chromatin and make DNA less accessible for gene expression. The researchers studied the effects of entinostat, a class I HDAC inhibitor, on the transformation from pancreatic stellate cells to fibroblasts in vitro. Under normal conditions, culturing pancreatic stellate cells from mouse pancreas for a few days transforms them into proliferating fibroblasts that promote tumor growth and fibrosis. Entinostat inhibited the induction of fibroblast and proliferation markers and downregulated the expression of genes upregulated during pancreatic stellate cell activation, suggesting that HDAC facilitate the epigenetic changes necessary for the pro-tumorigenic fibroblast transition.
When the researchers transplanted pancreatic tumors with HDAC-deficient fibroblasts, they found that the tumors had decreased fibroblast content and lower collagen deposition, indicating less fibrotic and pro-tumorigenic stroma. In a mouse model of pancreatic cancer, entinostat reduced tumor burden by 41 percent and extended survival by 35 percent.
Combining entinostat with gemcitabine, a standard chemotherapeutic agent for pancreatic cancer, resulted in enhanced therapeutic benefits with a 53 percent reduction in tumor burden and a 60 percent increase in survival rates in mice with pancreatic cancer. “We were able to reduce the proliferation of the tumor and open up the environment so drugs could come in more efficiently,” said Evans.
An analysis of bulk tumor data from a patient cohort revealed an association between high HDAC activity and poor pancreatic cancer prognosis, suggesting that targeting HDAC could be a viable therapeutic strategy. HDAC activity could help stratify patients into different risk categories, which could inform more personalized approaches to therapy, tailoring treatments based on the molecular characteristics of each patient's tumor.
“Our goal is to get the right genes to turn off or on using HDAC inhibitors,” said Evans. “That's going to apply to probably multiple other cancers, including colon and liver.” There's potential for combining HDAC inhibitors with other treatments, such as immunotherapies. Kalluri added, “I would like to see more studies on how HDAC inhibition impacts the immune system and how that could inform a combination therapy.”
References
- Jin, G. et al. Molecular Mechanism of Pancreatic Stellate Cells Activation in Chronic Pancreatitis and Pancreatic Cancer. J Cancer 11, 1505–1515 (2020).
- Liang, G. et al. Inhibiting stromal Class I HDACs curbs pancreatic cancer progression. Nat Commun 14, 7791 (2023).