Abstract 2703: Effect of combination of calcipotriol with paclitaxel on pancreatic ductal adenocarcinoma orthotopic mouse model

Abstract Pancreatic ductal adenocarcinoma (PDAC) remains one of the leading causes of cancer-related mortality in the United States, with a dismal 5-year overall survival rate of less than 11%. The progression and treatment resistance of PDAC is heavily influenced by its dense stromal environment, acting as a physical and biochemical barrier, limiting the effective delivery of therapeutics to tumor tissues. This stromal barrier significantly contributes to suboptimal drug efficacy and poor therapeutic outcomes. Calcipotriol (Cal), a known modulator of tumor stroma, may disrupt this barrier and enhance drug delivery to tumors. In this study, we investigated the combination of Cal with paclitaxel (PTX), a commonly used chemotherapeutic agent, to evaluate its ability to improve therapeutic efficacy and drug distribution in a PDAC mouse model. Using an orthotopic Kras* C57bl/6 mouse model of PDAC, we assessed the pharmacokinetics, biodistribution, and antitumor effects of Cal, PTX, and the combination (Cal/PTX). Mice were randomized into four treatment groups: Cal/PTX combination therapy (3 doses of 2 mg/kg /20 mg/kg and 3 doses of 1 mg/kg/10 mg/kg) (N=3), Cal alone (2 mg/kg) (N=3), PTX alone (20 mg/kg) (N=3), and vehicle control (N=4). All treatments were administered intraperitoneally with the solvent Ethanol:Cremophore:Saline (1:1:8) as vehicle and a dosing regimen of 3 days a week (day on day off) for 2 weeks. Tumor intensity was monitored over two weeks using bioluminescence imaging with an IVIS system. Drug concentrations in blood and tumor tissues were quantified using a validated LC-MS/MS method with a lower limit of quantification (LLOQ) of 0.5 ng/ml. In the Cal/PTX group, tumor growth was effectively inhibited, with a 100% response rate observed after 6th dose. Conversely, in the groups treated with Cal or PTX alone, tumor growth continued in 2 out of 3 mice, suggesting limited efficacy of the single agents. Similarly, 3 out of 4 mice showed no signs of tumor regression in the vehicle group. Biodistribution studies further supported these findings, with significantly higher accumulation of both Cal and PTX at the tumor site in the combination group compared to single-agent groups, indicating improved tumor-specific delivery. In the tumor, the mean concentrations (ng/g) (±SD) of Cal and PTX in the combination group were 98.08 ± 55.5 and 147.4 ± 45.07, respectively, compared to 3.71±2.33 and 52.46 ± 21.25 in the alone group. These findings highlight the potential of the Cal/PTX combination therapy to overcome stromal barriers and enhance drug delivery and antitumor efficacy in PDAC. Ongoing work focuses on developing a co-formulated polymeric micelle system (M-Cal/PTX) to be tested on Kras* mouse model to enhance drug delivery further, maximize therapeutic outcomes, and overcome drugs’ associated toxicity. This novel approach could pave the path for more effective treatment strategies for PDAC. Citation Format: Fatima Dagher, Mikayla Skillman, Guodong Zhang, Lu Dai, Amir Mohammad Gholizadeh, Chun Li, Diana S-L Chow. Effect of combination of calcipotriol with paclitaxel on pancreatic ductal adenocarcinoma orthotopic mouse model [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 2703.