High‐grade glioma is an aggressive cancer that occurs naturally in pet dogs. Canine high‐grade glioma (cHGG) is treated with radiation, chemotherapy or surgery, but has no curative treatment. Within the past eight years, there have been advances in our imaging and histopathology standards as well as genetic charactereization of cHGG. However, there are only three cHGG cell lines publicly available, all of which were derived from astrocytoma and established using methods involving expansion of tumour cells in vitro on plastic dishes. In order to provide more clinically relevant cell lines for studying cHGG in vitro, the goal of this study was to establish cHGG patient‐derived lines, whereby cancer cells are expanded in vivo by injecting cells into immunocompromized laboratory mice. The cells are then harvested from mice and used for in vitro studies. This method is the standard in the human field and has been shown to minimize the acquisition of genetic alterations and gene expression changes from the original tumour. Through a multi‐institutional collaboration, we describe our methods for establishing two novel cHGG patient‐derived lines, Boo‐HA and Mo‐HO, from a high‐grade astrocytoma and a high‐grade oligodendroglioma, respectively. We compare our novel lines to G06‐A, J3T‐Bg, and SDT‐3G (traditional cHGG cell lines) in terms of proliferation and sensitivity to radiation. We also perform whole genome sequencing and identify an NF1 truncating mutation in Mo‐HO. We report the characterization and availability of these novel patient‐derived lines for use by the veterinary community.
Glioblastoma (GBM) is the most lethal primary brain tumor, with a 5 year survival rate of only 5%. The standard of care for GBM is maximal surgical resection of the tumor, followed by irradiation and chemotherapy. Despite treatment, tumors recur in almost 100% of patients. There are subpopulations of cells in GBM that are radioresistant and chemoresistant, and new treatments will need to inclusively target these cells. KIF11 is a mitotic protein that drives bipolar spindle formation and is crucial for successful completion of mitosis. We previously reported that KIF11 is overexpressed in GBM over normal brain tissue, and that inhibiting KIF11 in a patient-derived xenograft (PDX) GBM mouse model increased survival. However, in this model, tumors recurred after treatment was stopped, indicating that treatment may have had a cytostatic effect, rather than cytotoxic. Importantly, it has been reported that cells are most vulnerable to irradiation when they are in mitosis. Because using a KIF11 inhibitor arrests cells in mitosis, we hypothesized that combining irradiation and a KIF11 inhibitor would radiosensitize GBM cells, and lead to greater tumor cell death. In this study, we found that combination therapy increased cell death over vehicle or either treatment used alone in patient-derived GBM cells in vitro. Additionally, we found that inhibiting KIF11 combined with radiotherapy increased survival over vehicle or monotherapy in orthotopic PDX models. Our results demonstrate that combining KIF11 inhibitors with radiotherapy is a promising potential therapy for GBM.
The cover image is based on the Original Article Establishment and characterization of two novel patient‐derived lines from canine high‐grade glioma by Morgan S. Schrock et al., https://doi.org/10.1111/vco.12912. image
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