Abstract A117: Co-priming sonic hedgehog inhibitor sonidegib with plerixafor induces tumor microenvironment transformation that enhances fluorescent nanoparticle deposition in pancreatic tumor xenograft

Abstract Nanomedicines have seen widespread use in several malignancies including pancreatic cancer where standard-of-care chemotherapy regimens regularly employ nanomedicines including nab-paclitaxel and liposomal irinotecan. However, a small fraction of the administered dose reaches the tumor, and that fraction rarely perfuses beyond the tumor periphery due to the dense desmoplasia reaction from cancer-associated fibroblasts. Sonidegib, an inhibitor of the sonic hedgehog signaling axis, transiently deconstructs delivery barriers in pancreatic tumor xenografts by targeting myofibroblasts thus priming tumors for nanoparticle deposition. However, these effects are heterogeneous and often short-lived due to rebound fibrosis. We demonstrated that co-priming with plerixafor, an inhibitor of the C-X-C motif type-4 receptor, prevents priming resistance onset via several mechanisms including inhibition of hedgehog signaling crosstalk between tumor and stromal cells and reversal of epithelial-to-mesenchymal transition. Plerixafor was shown to block rebound hedgehog ligand production by downstream MEK-ERK signaling which interrupted hedgehog signaling feedback to cancer-associated fibroblasts. Immunofluorescence staining revealed decreased expression of classical mesenchymal markers in co-cultures of pancreatic cancer cells and fibroblasts treated with plerixafor after repeated exposure to sonidegib. Importantly, when administered concurrent with sonidegib, plerixafor increased deposition of fluorescently-labeled liposomes suggesting an enhancement of the tumor priming effect compared to sonidegib priming alone. We surmise that co-priming via sondegib and plerixafor may enhance exposure to nanoparticle-associated chemotherapeutics in highly desmoplastic pancreatic tumors compared to sonidegib priming alone. This combination may be explored further to probe anti-tumor efficacy when combined with nanoparticle-associated chemotherapy currently employed for treating pancreatic cancer. Future investigations will evaluate the pro-immune effects of plerixafor in this co-priming strategy to improve outcomes with contemporary immune checkpoint therapeutics. Citation Format: Jonathan R. Perri, Andrea Serratore, Ninfa L. Straubinger, Robert M. Straubinger. Co-priming sonic hedgehog inhibitor sonidegib with plerixafor induces tumor microenvironment transformation that enhances fluorescent nanoparticle deposition in pancreatic tumor xenograft [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(18_Suppl_3):Abstract nr A117.