Abstract 3047: Glycan-targeted therapy for effective treatment of pancreatic cancer

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Abstract Patients with the most common pancreatic malignancy, pancreatic ductal adenocarcinomas (PDAC), typically present with advanced disease and their cancer progresses 6-12 months after treatment with the front-line regimen, FOLFIRINOX (5-fluorouracil, oxaliplatin, irinotecan and leucovorin). Therefore, there is a critical need for new and effective treatment regimens for PDAC patients. The novel polynuclear platinum agent, Triplatin (BBR3464), showed objective responses in a subset of patients, including a pancreatic cancer patient with liver metastasis in clinical trials. Although Triplatin did not advance beyond Phase II, our new understanding of its mechanism of action supports the rationale for its re-examination against tumors expressing high levels of glycosaminoglycans (GAGs), specifically chondroitin-4-sulfate (C4S). C4S is a tumor-specific GAG attached to proteoglycans such as CD44, glypicans and syndecans, expressed on the cell surface and in tumor stroma. The positive charge of Triplatin increases its binding affinity to negatively charged GAGs, which facilitates drug accumulation into the tumor cells and increases the level of platinum-DNA adducts. Recent studies suggest that overexpression of GAGs, particularly CS, contributes to the dense fibrotic stroma associated with PDAC, and resistance to chemotherapeutics and new immunotherapeutic agents. Our preliminary data indicates that alterations in the expression of GAG levels in PDAC cell lines affect the cytotoxicity and cellular uptake of Triplatin. First, we show Triplatin is generally more active than oxaliplatin against human and mouse PDAC cell lines. Secondly, a GAG-deficient CHX1990 cell line (CRISPR KO of β-1, 4-galactosyltransferase 7 (B4GalT7), verified by reduction in binding of CS-binding peptide, rVAR2-V5, shows a correlative loss in cytotoxicity. Interestingly, the reduction in Triplatin Pt-DNA adduct formation observed in the CHX1990 B4GalT7 KO (HS and CS deficient), CSGalNAcT1/2 KO (CS deficient) and CHST 11/12 KO (chondroitin-4-sulfate (C4S) deficient) is at similar levels, suggesting DNA platination by Triplatin is dependent specifically on C4S. Third, we show significant activity of Triplatin against high GAG-expressing PDAC PDX and mouse CHX1990 models in vivo. Finally, we show high GAG expression in PDAC patient samples vs normal tissues, highlighting the potential of GAG-targeted platinum therapy. Together, our results show that GAGs may provide a viable biomarker for Triplatin in PDAC patients, producing a significant clinical advantage over oxaliplatin in this setting. A more active platinum would not only increase response rates and durations of response, but also avoid the toxicity of relatively inactive therapy. Citation Format: Erica J. Peterson, 1 Vignesh Vudatha, 1 Vashti Bandy, 1 Praveen Bhoopathi, 1 Arunima Punjala, 1 Thomas M. Clausen, 2 Jennifer E. Koblinski, 1 Chunqing Guo, 1 Larisa Litovchick, 1 Jose G. Trevino, 1 Nicholas P. Farrell1. Glycan-targeted therapy for effective treatment of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3047.

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