nintedanib and Osteosarcoma

It is well established that fibrotic remodeling of the tumor microenvironment favors tumorigenesis, but whether fibrosis underlies malignant progression in other ways is unclear. Here, we report that adaptive myofibroblastic reprogramming of osteosarcoma stem cells (OSCs) results in a critical advantage when establishing lung macro-metastases and spheroid growth but does not affect the growth of primary lesions or monolayer cultures. FGFR2 signaling in OSCs initiates fibrosis, whereas the resultant fibronectin (FN) auto-deposition sustains fibrogenic reprogramming and OSC growth, resembling the process employed by non-malignant myofibroblasts to cause tissue fibrosis. Furthermore, we provide evidence that nintedanib targets the pan FGFR-FN axis to disrupt lung metastasis without affecting the bone lesion growth of OSCs. Thus, myofibroblastic reprogramming of human OSCs in the lungs might represent a druggable trait for treating a deadly metastatic complication.

Topics: Animals; Cellular Reprogramming; Female; Fibronectins; Fibrosis; Hep G2 Cells; Humans; Indoles; Lung Neoplasms; MCF-7 Cells; Mice, Inbred NOD; Mice, SCID; Myofibroblasts; Neoplastic Stem Cells; Osteosarcoma; Protein Kinase Inhibitors; Receptor, Fibroblast Growth Factor, Type 2

Fibroblast growth factor receptor (FGFR) inhibitors like ponatinib and nintedanib are clinically approved for defined cancer patient cohorts but often exert dose-limiting adverse effects. Hence, we encapsulated the FGFR inhibitors ponatinib, PD173074, and nintedanib into polylactic acid nanoparticles and liposomes to enable increased tumor accumulation/specificity and reduce side effects. Different methods of drug loading were tested and the resulting formulations compared regarding average size distribution as well as encapsulation efficiency. Appropriate encapsulation levels were achieved for liposomal preparations only. Nanoencapsulation resulted in significantly decelerated uptake kinetics in vitro with clearly decreased short-term (up to 72 h) cytotoxicity at higher concentrations. However, in long-term clonogenic assays liposomal formations were equally or even more active as compared to the free drugs. Accordingly, in an FGFR inhibitor-sensitive murine osteosarcoma transplantation model (K7M2), only liposomal but not free ponatinib resulted in significant tumor growth inhibition (by 60.4%) at markedly reduced side effects.

Topics: Animals; Bone Neoplasms; Cell Proliferation; Enzyme Inhibitors; Humans; Imidazoles; Indoles; Liposomes; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, SCID; Nanoparticles; Osteosarcoma; Pyridazines; Receptor, Fibroblast Growth Factor, Type 1; Therapeutic Index; Tumor Cells, Cultured; Xenograft Model Antitumor Assays