Investigating the therapeutic potential of a nanocrystal PRMT5 inhibitor in pancreatic ductal adenocarcinoma

Persistent inflammation is a defining feature of pancreatic ductal adenocarcinoma (PDAC), largely driven by sustained activation of the NF-κB signaling pathway. Disruption of NF-κB regulatory mechanisms contributes significantly to this chronic activation. Protein arginine methyltransferase 5 (PRMT5), a known promoter of tumorigenesis in several cancers, including PDAC, colorectal, and breast, has emerged as a promising therapeutic target. Clinical data reveal that PDAC patients with high PRMT5 expression have significantly shorter median survival, underscoring its prognostic and therapeutic relevance. Our lab has been developing small-molecule inhibitors targeting PRMT5. Among these, our patented compound, PR5-LL-CM01 (CM01), has shown superior anti-tumor efficacy and reduced toxicity in PDAC models compared to the commercially available PRMT5 inhibitor EPZ015666. However, CM01's poor water solubility poses a challenge for clinical translation. To address this, we aim to enhance its water dispersibility and bioavailability by formulating CM01 as an albumin-coated nanocrystal (NC) (Abxtal). Preliminary studies confirmed successful production and physicochemical characterization of CM01 NCs, which have an optimized particle size (Z-average ~87 nm) and can be stored at -20ºC as lyophilized solid for at least three months. In this project, we assess the therapeutic potential of CM01 NC in vitro and in vivo. We hypothesize that CM01 NC more effectively inhibits PRMT5-mediated NF-κB signaling and associated oncogenic processes than unformulated CM01, and that it synergizes with gemcitabine (Gem) to suppress PDAC progression. Supporting this hypothesis, CM01 NC showed equal or greater inhibition of PDAC PANC1 and MIA PaCa2 cell growth compared to CM01, and more effectively suppressed 3D spheroid growth and cell migration in vitro. CM01 NC also outperformed CM01 in reducing NF-κB transcriptional activity, with comparable reductions in NF-κB target genes (TNF-alpha and IL-8) per qPCR assays. Additionally, Chou-Talalay analysis demonstrated that CM01 NC exhibits synergistic activity with Gem. We are now transitioning to in vivo studies to evaluate the pharmacokinetics and therapeutic efficacy of CM01 NC, both as a monotherapy and in combination with Gem, using PDAC models. This study may establish CM01 NC, alone or with Gem, as a promising therapeutic strategy, and could lay the foundation for clinical development of CM01 NC-based treatments for PDAC.