Mentor Name: John Bushweller

Osteosarcoma is a primary bone cancer principally occurring in children and adolescents. Most cases of osteosarcoma develop in children between the ages of 10-16 years. Treatment for osteosarcoma consists of surgery combined with traditional cytotoxic chemotherapy (doxorubicin and cisplatin ± methotrexate). The five-year survival rates typically exceed 60% at most treatment centers. It is important to note that for patients with metastatic or recurrent disease (30-40% of patients), survival has not improved and has remained at the 20% level. This highlights the clear need for new, targeted approaches to the treatment of osteosarcoma. Furthermore, as the majority of these patients are young, the long term neurological and cardiovascular deficits caused by these traditional cytotoxic chemotherapy approaches result in long-term health problems for these patients. For all these reasons, the development of targeted therapies with limited or no off target toxicity would be highly advantageous for the treatment of these patients. Huang and co-workers showed that knockdown of the transcription factor RUNX2 leads to apoptosis of osteosarcoma cells while having no impact on the apoptosis or proliferation of normal mesynchymal stem cells (MSCs). RUNX2 is a member of a family of transcription factors (RUNX1, 2, 3) all of whom form a complex with the partner protein CBFß. Binding of CBFß relieves autoinhibition of the RUNX family members making them bind to DNA with higher affinity. CBFß binding is essential for the function of RUNX2 and other family members. Indeed, Huang and co-workers also showed that CBFß is over-expressed in osteosarcoma cells compared with normal MSCs. Based on this data, the Bushweller lab is developing covalent CBFß inhibitors as a novel approach for the treatment of osteosarcoma. A library of covalent CBFß inhibitors has been synthesized and new analogs are being made to optimize the ADMET properties and increase the likelihood of efficacy in vivo.