Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers, with limited treatments and a 5-year survival rate of 13%. A key driver of therapeutic resistance in PDAC is the dense desmoplastic stroma which makes up 80-85% of the tumor bulk and creates a physical and biological barrier that impairs perfusion, excludes drugs and promotes immune evasion. We comprehensively evaluated the antitumor activity of polymeric micelles encapsulating cyclopamine and paclitaxel (ONP-001). Cyclopamine (CPA) is a hedgehog (Hh) pathway inhibitor that targets stroma and cancer stem cells (CSC), and paclitaxel (PTX) is a chemotherapeutic agent that interferes with the cell cycle and triggers apoptosis. Methods: CPA and PTX were encapsulated in a selected ratio in micelles (45±10 nm in size) for improved bioavailability and tumor targeting. In vivo efficacy, tissue distribution, and mechanistic studies were conducted in a syngeneic Kras* orthotopic tumor model in mice with palpable tumors. Stromal modulation was assessed following three consecutive intravenous (IV) doses of ONP-001. Comparative tissue distribution of ONP-001 vs. nab-paclitaxel in tumor, blood, liver and spleen were measured after six doses over two weeks of equivalent paclitaxel doses. Comparative antitumor efficacy was examined after 8 weeks of IV administration of ONP-001 thrice weekly, at two dose levels, vs. nab-paclitaxel plus gemcitabine. Results: IV administration of ONP-001 achieved sustained, pharmacologically active levels of both CPA and PTX in tumors 24 hours post dose, with tumor concentrations significantly higher than blood. Early signs of tumor remodeling included reduced fibrosis, improved perfusion, decreased hypoxia, and downregulation of pro-tumor genes—potential mechanisms ONP-001 may utilize to overcome resistance in PDAC. Compared to nab-paclitaxel, ONP-001 delivered greater intratumoral PTX levels, at equivalent doses, without increased off-target accumulation. In a Kras driven syngeneic mouse model, refractory to gemcitabine + nab-paclitaxel, ONP-001 significantly improved median survival at two dose levels (p0. 01 and p0. 001). Conclusion: ONP-001 preferentially delivers CPA and PTX to tumors, modulates the tumor stroma to increase blood flow, and decrease fibrosis and hypoxia, and kills cancer cells, creating a tumor microenvironment that is less supportive of cancer growth. ONP-001 significantly extended survival compared to gemcitabine + nab-paclitaxel in a resistant disease model of PDAC, suggesting potential for clinical translation. Ongoing studies are exploring synergy with immunotherapy and optimal dosing strategies to support IND-enabling development. Citation Format: Qiu-Xu Teng, Guodong Zhang, Emanuel Baltrip, Ping Pan, Diana S-L. Chow, Guorong Ma, Leslie S. Sloan, Chun Li. Dual mechanism nanomedicine targeting drug resistance in pancreatic ductal adenocarcinoma (PDAC) abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85 (18Suppl₃): Abstract nr A121.
Teng et al. (2025) studied this question.