Targeting mitochondrial adaptive response in pediatric bone sarcomas
Mentor Name: Poul Sorensen
Current treatments for patients with localized osteosarcoma (OS) involving surgery and chemotherapy have a survival rate of ~75%; however, only 25% of patients diagnosed with refractory and metastatic OS will survive for 5 years. We have recently demonstrated that OS cells rely on their antioxidant capacity to mitigate the oxidative stress encountered during the metastatic process, which supports OS tumor growth and lung metastasis. Recent studies have demonstrated that the compound thiostrepton irreversibly binds and inhibits proteins downstream of the major antioxidant transcription factor NRF2, namely PRDX3 and PRDX5, resulting in cancer cell death. It was also demonstrated that thiostrepton can reduce tumor growth of breast, mesothelioma, and pancreatic cancer cells. We hypothesize that targeting OS antioxidant response with thiostrepton will increase their sensitivity to the stresses encountered throughout the metastatic process and prevent OS progression. We propose to evaluate in vitro the effects of thiostrepton in combination with ROS-inducers on cell proliferation and survival to validate its anti-metastatic potential on OS cells. As current standard-of-care therapies for the treatment of metastatic OS rely on toxic chemotherapy drug treatment, it is crucial to identify novel, safe therapeutic strategies for the treatment of advanced OS.
