Dissecting and Targeting the Wnt Signaling Pathway in Metastatic Osteosarcoma
Metastatic disease is responsible for about 90% of all cancer related deaths. Metastasis is when a patient's cancer has spread throughout the body and is not just located in one single tissue or organ. For children afflicted with metastatic osteosarcoma, the most common bone tumor in the pediatric population, it often means a very aggressive cancer that is associated with an extremely poor outcome.
Unfortunately one reason for this unacceptable outcome is due to not understanding the biology of the metastatic state and determining better treatment options.
Recently our laboratory has created a new mouse model of metastatic osteosarcoma that mimics the human tumor development and progression. Using the tumors from this model, we have been able to analyze genes and determine pathways that are abnormally functioning, including the identification of key alterations in the Wnt signaling pathway in metastatic tumors.
We have specifically identified and studied Wnt-related genes previously not associated with metastatic osteosarcoma. One identified gene, known as NKD2, is a critical inhibitor of the Wnt pathway and its presence is diminished in the metastatic tumors. When placed back into human metastatic osteosarcoma cells, we proved that NKD2 biologically contributes to controlling the development of metastatic disease.
We propose to identify the specific genes and pathways that NKD2 controls in metastatic osteosarcoma and their role in the progression of the disease. In addition, we propose to test new drugs that target the activity of the Wnt signaling using our mouse model that spontaneously develops metastatic osteosarcoma.