It is well established that tumor expression of Gli2, a Hedgehog family transcription factor, contributes to tumor-induced bone disease. Our previous studies investigating genetic inhibition of Gli2 expression in tumor cells have shown promise for the development of therapeutics. While many groups have focused on developing upstream Hedgehog inhibitors for soft-tissue tumors that aberrantly express Gli proteins, we have previously demonstrated that the expression of Gli2 in tumor-induced bone disease is not always regulated by canonical Hedgehog signaling, therefore upstream inhibitors will not be effective. In vitro studies have identified several efficacious small molecule Gli inhibitors, but they are hydrophobic and difficult to deliver in vivo. We hypothesized that drug delivery strategies using micro/nanoparticles to encapsulate Gli inhibitors would significantly reduce tumor-induced bone destruction. Therefore, we loaded polypropylene sulfide (PPS) microparticles with the Gli2 antagonist GANT58 to inhibit Gli2 locally. The GANT58-loaded PPS microparticles (GANT58-MP) were fabricated using an oil-in-water emulsion method, creating spheroid particles (average size of 4.1±3 μm verified by SEM) that exhibited ROS-regulated controlled release. Since local bony invasion is a serious consequence in invasive oral cancer and Gli2 is overexpressed by these tumors, we initially tested the GANT58-MP in a model of oral cancer invasion into the mandible. Specifically, bony-invasive CAL27 oral squamous cell carcinoma cells were injected into the masseter muscle of athymic nude mice. GANT58-MP treatment significantly reduced bone destruction by greater than twofold (P=0.0096). In order to target bone metastatic disease, we have developed similar nanoparticle encapsulation approaches for systemic treatment. Preliminary studies indicate a reduction in lesion area after drug treatment, as well as a significant increase in uptake of the drug in bone with tumors as opposed to non-tumor bone (P=0.0176). Thus, these results suggest that targeted Gli inhibitors are a promising reducing tumor-induced bone disease.
14 - 17 May 2016
European Calcified Tissue Society