It is estimated that the year 2017 will bring about 1,688,780 new cancer diagnoses in the United States. Among those, approximately 1000 new cases will be of osteosarcoma, a primarily pediatric bone tumor, and the most common primary bone malignancy. The improved treatment of this rare cancer is a necessity because of its propensity for afflicting young children and adolescents, its traumatic effect on quality of life among survivors, and the lack of improvement in patient outcomes in the last several decades.

The objective of this work is to assess the value of Wnt-targeted chemotherapies in the context of pre-clinical models of chemotherapy-naïve and resistant osteosarcoma. To achieve this goal, the following aims were pursued:​ AIM 1 – investigate the mechanism of action of the Wnt inhibitor FH535 in osteosarcoma, and AIM 2 – pursue Wnt inhibition as a means to sensitize chemotherapy resistant osteosarcoma.

The findings from these studies are that response to Wnt inhibition by currently available small molecules is highly variable in osteosarcoma. Significant growth inhibition by single agent chemotherapy is observed in some cell lines and with some molecules. Strong sensitization to doxorubicin is evident with the small molecule IWR-1-endo, yet only in doxorubicin resistant cells. The data and conclusions which are presented here give further insight into the molecular mechanism and specificity of Wnt targeting small molecules in the context of osteosarcoma.