利用肿瘤微环境GAGs的表达增强胰腺腺癌中基于铂的治疗

Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed at an advanced stage, with most patients experiencing disease progression within 6-12 months following frontline FOLFIRINOX (5-fluorouracil, oxaliplatin, irinotecan, leucovorin), underscoring the need for more effective treatment strategies. Recent evidence suggests that overexpression of glycosaminoglycans (GAGs)-particularly chondroitin-4-sulfate (C4S)-contribute to the dense, fibrotic stroma characteristic of PDAC and tumor resistance to chemotherapy. C4S, a tumor-associated GAG linked to proteoglycans such as CD44, glypicans, and syndecans, is prominently expressed on the cell surface within the tumor stroma. Our studies demonstrate that C4S expression predicts PDAC tumor sensitivity to the Phase II polynuclear platinum agent, Triplatin (BBR3464). The highly cationic structure of Triplatin enhances its binding affinity for negatively charged GAGs, promoting drug accumulation and increased formation of platinum-DNA adducts. These findings provide a strong mechanistic rationale for re-evaluating Triplatin in tumors with high GAG expression, particularly C4S. Our preliminary data shows that modulating GAG levels in PDAC cell lines alters both the cytotoxicity and cellular uptake of Triplatin. First, Triplatin exhibits greater cytotoxicity than oxaliplatin in the CHX1990 mouse cell line, an established model of PDAC derived from the Kras(G12D)/Trp53 null/Pdx1-cre (KPC) model. Second, a GAG-deficient CHX1990 cell line, B4GalT7 (CRISPR KO of beta-1,4-galactosyltransferase 7), verified by reduced binding of the CS-binding peptide rVAR2-V5, shows a correlative loss in cytotoxicity. Finally, Triplatin significantly suppresses CHX1990 tumor growth in vivo with minimal changes in body weight relative to untreated controls. Collectively, these findings suggest that GAGs serve as a viable biomarker for Triplatin response in PDAC and may confer significant therapeutic advantage over oxaliplatin in this context. To further support our studies, we are investigating Triplatin's mechanism of action through proteomic analyses that assess intracellular drug accumulation impacts on DNA repair proteins and apoptosis pathways. To complement this work, spatial transcriptomics will be used to map gene expression within the tumor microenvironment, providing insight into how Triplatin distribution corresponds with tumor cell responses. Additionally, synergy studies examining Triplatin in combination with standard-of-care therapies will help determine its therapeutic effectiveness. Together, these integrated approaches aim to advance Triplatin as a promising therapy for treatment of PDAC.