IAP antagonists for osteosarcoma

Although most cancers tend to occur in older people, the bone cancer osteosarcoma typically arises in adolescents and young adults. Unfortunately, cure rates for this cancer have improved little in the last four decades. Currently, only 59% of Australians survive more than five years after being diagnosed with osteosarcoma, and only around a quarter of patients with metastatic disease survive for five years or more. The majority of osteosarcoma survivors suffer from on-going treatment-related disease and disability. Some of the more severe side effects include the physical and psychological impacts of amputation, cardiac damage caused by the chemotherapy doxorubicin, and therapy-related second cancers provoked by DNA damaging chemotherapy.

We are investigating the potential for direct apoptosis inducers to treat osteosarcoma more safely and effectively. We have shown that drugs targeting Bcl-2 or IAP proteins are non-mutagenic. This implies that, if these drugs could eliminate osteosarcomas, they may spare survivors the risk of developing therapy-related cancers later in life. In collaboration with Carl Walkley (St Vincent's Institute) we have found that osteosarcoma cells respond to IAP antagonists in vitro. In ongoing work, we are dissecting the molecular pathways by which IAP antagonists kill osteosarcoma cells, and assessing the efficacy of these drugs in vivo.