01503-A: Rational Development of Targeted Therapy - Aurora Kinase Inhibition in Osteosarcoma
Grant Status: Closed
Project SummaryAurora Kinases (AKs) are essential regulators of cell division in all animals from yeast to man. The normal mechanisms that control these proteins may be lost in cancer: various human tumors express very high levels of AKs, which are associated with poor prognosis. No studies have examined AKs in dogs, but their potential importance was highlighted by recent data from the investigator's group; supported by grant CHF 947, which identified a "gene signature" with different levels of expression in dogs with bone cancer that had "better" vs. "poor" outcomes. A component of this signature included genes that control cell division where the key elements are AKs A and B. The hypothesis under test was that osteosarcoma cells with high AK expression would be more sensitive to targeted inhibition of these proteins than cells with low AK expression. Targeted AK inhibitors are available and have completed preliminary toxicity testing for human cancer patients. However, targeted AK inhibitors had never been tested against canine cells. To test the hypothesis, the investigators examined how inhibition of AKs using small molecules affects osteosarcoma cell proliferation and survival. Given the safety profile of AK inhibitors, documentation of efficacy to kill tumor cells at a relevant concentration would provide impetus for translation of this class of drugs to treat dogs with bone cancer. Their results show that AK inhibitors promote cell death of dog bone cancer cells in laboratory culture. However, these cells are rather resistant to these compounds, especially when compared to a variety of human cancers that are targets for this treatment. It is unclear if the resistance is a characteristic of bone cancer itself (the most likely explanation), or if resistance is related to the canine origin of the tumors (very unlikely). The investigators documented mechanisms that potentially mediate resistance, and so conclude that these compounds should be evaluated as part of combined approaches that target resistance (protocols could include combination with conventional chemotherapy agents that are currently used to treat dogs with bone cancer).
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