Dr Avila’s presentation focused on the potential of targeting protein arginine methyltransferases (PRMTs) in the treatment of cholangiocarcinoma (CCA). He highlighted the role of epigenetic mechanisms in cancer progression and the potential of these enzymes as therapeutic targets. His research sheds light on how such regulatory processes influences tumor behavior and explores novel strategies to improve treatment outcomes for patients with CCA.
Epigenetic mechanisms regulate gene expression without changing the underlying DNA sequence. However, disruptions in these mechanisms have been increasingly implicated in cancer development, including in CCA. Dr Avila emphasized that non-mutational epigenetic changes are recognized as key players in enabling cancer cells to acquire hallmark traits. Several small-molecule inhibitors that target epigenetic regulators are already in clinical trials for various cancers.
Among the numerous epigenetic regulators, Dr Avila’s team focused on PRMTs, a family of 11 enzymes that modify arginine residues on histones and other proteins. Specifically, PRMT5 has garnered attention due to its involvement in multiple cancer-related processes, including histone methylation, cell signaling, splicing machinery, DNA damage repair, and antigen presentation. Importantly, tumor cells appear highly dependent on PRMT5 activity, with a 2- to 5-fold increase in enzymatic activity compared with normal cells.
The team identified a connection between PRMT5 activity and the methionine salvage pathway, involving the enzyme MTAP. Tumors with MTAP deletions accumulate methylthioadenosine, a strong inhibitor of PRMT5, creating synthetic lethality, where MTAP-deficient tumor cells are highly sensitive to PRMT5 inhibition.
Approximately 20% of analyzed CCA samples showed MTAP loss, making them prime candidates for PRMT5-targeted therapy. In addition, the combination of PRMT5 inhibitors with MTAP inhibitors showed synergistic effects in MTAP-positive cells, suggesting a broader therapeutic application.
Beyond PRMT5, researchers also investigated PRMT1, another member of the methyltransferase family responsible for most asymmetric arginine demethylation in cancer cells. PRMT1 inhibition reduced tumor growth and also enhanced immune responses by activating the cGAS-STING pathway, a critical component of the immune system that detects DNA damage.
In preclinical models, targeting PRMT1 had significantly improved antitumor immune responses. PRMT1 inhibition increased STING expression at both the mRNA and protein levels, along with downstream signaling events such as phosphorylation of IRF3, indicating strong pathway activation. Tumors showed reduced burden, increased immune cell infiltration, and enhanced DNA damage, potentially creating a more immunogenic tumor microenvironment.
The presentation concluded by highlighting the potential of targeting PRMTs to improve the efficacy of existing therapies, including chemotherapy and immunotherapy. The team’s findings suggest that PRMT inhibitors may suppress tumor growth and enhance immune system activation, potentially paving the way for more durable and effective treatments.
Although PRMT5 and PRMT1 are promising targets, Dr Avila stressed the importance of further research to understand their full therapeutic potential and to identify biomarkers that can potentially predict patient response. By combining PRMT inhibitors with other treatments, such as immune checkpoint inhibitors or chemotherapy, researchers hope to develop multipronged strategies to combat CCA’s resistance mechanisms.
Source: Avila MA. Protein arginine methyltransferases as potential pharmacological targets in cholangiocarcinoma. Presented at: 2026 Annual Cholangiocarcinoma Foundation Conference. May 1-3, 2026; Salt Lake City, UT.
To sign up for our newsletter or print publications, please enter your contact information below.
