Abstract 3141: Development and comprehensive preclinical evaluation of dual-drug polymeric micelles ONP-001 for PDAC and HCC

Introduction: Pancreatic ductal adenocarcinoma (PDAC) and hepatocellular carcinoma (HCC) remain the leading causes of cancer-related mortality, with poor outcomes. This study comprehensively evaluated the mechanisms of polymeric micelles co-encapsulating cyclopamine (CPA) and paclitaxel (PTX) (M-CPA/PTX, ONP-001) and the effectiveness against HCC and PDAC. The dual-drug delivery system targets embryonic signaling pathways, such as Hedgehog (Hh), which drives tumor progression and resistance. Methods: CPA and PTX were encapsulated in micelles (∼55 nm in size) to improve bioavailability and tumor concentrations. Preclinical experiments included in vitro assays for cytotoxicity, tumorsphere, and colony formation in both cancer cell lines. In vivo models included orthotopic Kras* cell implanted PDAC and spontaneous HCC in transgenic LAP-tTA/TRE-MYC mice. The antitumor efficacy was examined by intravenously injection of ONP-001 at 2.5, 5.0, and 7.5 mg/drug equivalent/kg thrice weekly for 4 weeks, as well as combination regimens with irreversible electroporation (IRE) and an immune checkpoint inhibitor. Survival, tumor burden, immune modulation, and cytokine profiles were analyzed using Kaplan-Meier survival curves, bioluminescence imaging, and multiplex cytokine assays. Results: In the PDAC model, ONP-001 significantly extended median survival at 2.5 mg equivalent drug/kg (p<0.01), 5.0 mg/kg (p<0.0001), and 7.5 mg/kg (p<0.05) compared untreated control. ONP-001 administered at 7.5 mg/kg displayed shorter median survival than 5.0 mg/kg suggesting that the optimal regimen tested was 5 mg/kg. ONP-001 reprogrammed tumor stroma, and reduced cancer stem cell (CSC)-associated tumorsphere formation. Combination of ONP-001 with IRE and anti-PD-1 further enhanced survival and immune infiltration, overcoming PDAC’s immunosuppressive microenvironment. In HCC, ONP-001 significantly inhibited tumor growth and colony formation. Tumor cytokine profiling revealed significant reductions in markers associated with CSC maintenance (e.g., IL-15, IL-33) and tumor progression, highlighting an anti-inflammatory effect on the tumor microenvironment. Studies in the transgenic HCC model also confirmed significantly greater antitumor efficacy for ONP-001, with no observed hepatotoxicity, compared to sorafenib treatment. Conclusion: ONP-001 was an effective therapeutic strategy for PDAC and HCC, targeting CSCs, modulating the stroma, and enhancing immunotherapy, at 5.0 mg/kg, TIW, with enhanced benefits when in combination regimens. Ongoing studies will further characterize the pharmacokinetics, tumor uptake and biodistribution of both drugs. The data supports further development of ONP-001 for potential future clinical development. Citation Format: Qiu-Xu Teng, Guodong Zhang, Lu Dai, Defeng Deng, Ping Pan, Diana S-L Chow, Guorong Ma, Peiying Yang, Chun Li. Development and comprehensive preclinical evaluation of dual-drug polymeric micelles ONP-001 for PDAC and HCC [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 3141.