gant58 and Bone-Neoplasms

Topics: Animals; Antineoplastic Agents; Bone Neoplasms; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Drug Screening Assays, Antitumor; Female; Humans; Ligands; Mice; Mice, Inbred C57BL; Mice, Knockout; Nanoparticles; Optical Imaging; Particle Size; Polymers; Pyridines; Surface Properties; Thiophenes; X-Ray Microtomography

Patients with advanced skeletal metastases arising from primary cancers including breast, lung, and prostate suffer from extreme pain, bone loss, and frequent fractures. While the importance of interactions between bone and tumors is well-established, our understanding of complex cell-cell and cell-microenvironment interactions remains limited in part due to a lack of appropriate 3D bone models. To improve our understanding of the influence of bone morphometric properties on the regulation of tumor-induced bone disease (TIBD), we utilized bone-like 3D scaffolds in vitro and in vivo. Scaffolds were seeded with tumor cells, and changes in cell motility, proliferation, and gene expression were measured. Genes associated with TIBD significantly increased with increasing scaffold rigidity. Drug response differed when tumors were cultured in 3D compared to 2D. Inhibitors for Integrin β3 and TGF-β Receptor II significantly reduced bone-metastatic gene expression in 2D but not 3D, while treatment with the Gli antagonist GANT58 significantly reduced gene expression in both 2D and 3D. When tumor-seeded 3D scaffolds were implanted into mice, infiltration of myeloid progenitors changed in response to pore size and rigidity. This study demonstrates a versatile 3D model of bone used to study the influence of mechanical and morphometric properties of bone on TIBD.

Topics: Animals; Bone Neoplasms; Cell Line, Tumor; Cell Movement; Female; Gene Expression Regulation, Neoplastic; Humans; Mice; Mice, Nude; Models, Biological; Neoplasm Metastasis; Neoplasm Proteins; Pyridines; Thiophenes; Tissue Scaffolds

Solid tumors frequently metastasize to bone and induce bone destruction leading to severe pain, fractures, and other skeletal-related events (SREs). Osteoclast inhibitors such as bisphosphonates delay SREs but do not prevent skeletal complications or improve overall survival. Because bisphosphonates can cause adverse side effects and are contraindicated for some patients, we sought an alternative therapy to reduce tumor-associated bone destruction. Our previous studies identified the transcription factor Gli2 as a key regulator of parathyroid hormone-related protein (PTHrP), which is produced by bone metastatic tumor cells to promote osteoclast-mediated bone destruction. In this study, we tested the treatment effect of a Gli antagonist GANT58, which inhibits Gli2 nuclear translocation and PTHrP expression in tumor cells. In initial testing, GANT58 did not have efficacy in vivo due to its low water solubility and poor bioavailability. We therefore developed a micellar nanoparticle (NP) to encapsulate and colloidally stabilize GANT58, providing a fully aqueous, intravenously injectable formulation based on the polymer poly(propylene sulfide)

Topics: Animals; Antineoplastic Agents; Apoptosis; Bone Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Carriers; Drug Liberation; Female; Gene Expression Regulation, Neoplastic; Humans; Mammary Neoplasms, Animal; Mesenchymal Stem Cells; Mice, Inbred C57BL; Mice, Knockout; Mice, Nude; Nanoparticles; Osteogenesis; Polymers; Pyridines; Thiophenes; Zinc Finger Protein Gli2