ABSTRACT
Spontaneously occurring soft tissue sarcoma (STS) is relatively common in canine cancer patients. Because of the similarities to human disease, canine STSs are a valuable and readily available resource for the study of new therapeutics. In this study, a canine patient-derived xenograft (PDX) model, CDX-STS2, was established. The CDX-STS2 model was engrafted and expanded for systemic administration studies with chemotherapeutic agents commonly used to treat STS, including doxorubicin, docetaxel and gemcitabine. Immunohistochemistry for drug-specific biomarkers and tumour growth measurement revealed tumour sensitivity to doxorubicin and docetaxel, whereas gemcitabine had no effect on tumour growth. Although many human PDX tumour models have been established, relatively few canine PDX models have been reported to date. CDX-STS2 represents a new STS PDX research model of canine origin that will be useful in bridging preclinical research with clinical studies of STS in pet dogs.
Subject(s)
Neoplasm Transplantation/veterinary , Sarcoma, Experimental/drug therapy , Sarcoma/veterinary , Animals , Antineoplastic Agents/therapeutic use , Biomarkers, Tumor , Disease Models, Animal , Dogs , Heterografts , Male , Mice , Mice, Nude , Neoplasm Transplantation/methods , Sarcoma/drug therapy , Sarcoma/pathology , Sarcoma, Experimental/pathologyABSTRACT
Dysregulated signal transduction through the notch pathway has been noted in human and mouse medulloblastoma studies. Gamma secretase inhibitors (GSIs) impair notch signaling by preventing the cleavage of transmembrane notch proteins into their active intracellular domain fragments. Previous studies have shown that GSI treatment caused apoptosis and impaired medulloblastoma cell engraftment in xenograft systems. In this study, we used in vivo genetic and pharmacologic approaches to quantify the contribution of notch signaling to sonic hedgehog (shh)-activated mouse medulloblastoma models. In contrast to prior in vitro studies, pharmacologic inhibition of notch pathways did not reduce the efficiency of medulloblastoma xenotransplantation nor did systemic therapy impact tumor size, proliferation, or apoptosis in genetically engineered mouse medulloblastoma models. The incidence and pathology of medulloblastomas driven by the SmoA1 transgene was unchanged by the bi-allelic absence of Notch1, Notch2, or Hes5 genes. These data show that notch signaling is not essential for the initiation, engraftment, or maintenance of sonic hedgehog pathway-driven medulloblastomas.
