Inhibition of Bromodomain Proteins Enhances Oncolytic HAdVC5 Replication and Efficacy in Pancreatic Ductal...

Area of Science:

• Oncolytic virotherapy
• Cancer epigenetics
• Pancreatic cancer research

Background:

• Pancreatic ductal adenocarcinoma (PDAC) is aggressive and develops resistance to standard treatments.
• Oncolytic Human AdenoViruses (HAdVs) show promise but face challenges like rapid elimination and limited tumor spread.
• Altering cellular epigenetic regulation is explored to enhance intratumoral virus levels.

Purpose of the Study:

• To screen epigenetic small molecule libraries for compounds that increase oncolytic virus gene expression and replication in PDAC.
• To validate the efficacy of identified epigenetic inhibitors, particularly those targeting bromodomain (BRD)-containing proteins, in combination with oncolytic viruses.

Main Methods:

• Screening of an enriched epigenetics small molecule library against PDAC cells.
• Validation of compounds using 3D co-culture models and in vivo xenografts.
• RNA sequencing (RNAseq) analysis to assess viral gene expression and host cell responses.

Main Results:

• Six compounds were validated for increasing viral gene expression and replication.
• Bromodomain (BRD)-containing protein inhibitors, especially BRD4 inhibitors, significantly enhanced oncolytic virus efficacy (Ad5, Ad∆∆, Ad-3∆-A20T).
• RNAseq revealed increased viral E1A expression, altered cell cycle and inflammatory factors, and reduced oncogene expression (c-Myc, Myb).

Conclusions:

• Epigenetic inhibitors, particularly BRD4 inhibitors, represent a novel strategy to enhance oncolytic virotherapy for PDAC.
• Combination therapy with tumor-selective viruses (Ad∆∆, Ad-3∆-A20T) and epigenetic inhibitors can overcome treatment resistance.
• This approach facilitates elimination of cancer and stromal cells, potentially improving immune cell infiltration after systemic delivery.