Osteosarcoma predominantly affects rapidly growing bones in children and adolescents and accounts for the majority of deaths from bone tumors, which are the third most common cause of cancer-related deaths in adolescents. Despite aggressive chemotherapeutic and surgical therapies, the survival rate is only 25% for patients who present with lung metastasis and 60-70% for those without detectable metastasis. Our goal is therefore to identify novel therapeutic agents that block the growth of lung metastases __ the lethal process in osteosarcoma. Repurposing of drugs that are already approved for clinical use in other cancers will substantially increase the likelihood of identifying safe and effective therapeutics and reduce the time and expense associated with traditional drug development. This is especially attractive for relatively rare cancers, including osteosarcoma, where there is limited commercial interest. However, most drugs that are already approved for other cancers have not been well characterized in osteosarcoma. This proposal therefore focuses on the NCI panel of 114 FDA-approved anti-cancer drugs. 3D tumor models are the best in vitro platforms for evaluating drug effects on growth of metastases. We have therefore recently developed improved osteosarcoma 3D in vitro platforms. One platform assesses growth of early micro-metastases by interrogating small non-adherent colonies embedded in a collagen gel. The second platform assesses growth of later micro-metastases by interrogating larger sarcospheres with higher cell density. To identify drugs that are effective at both stages, both 3D platforms will be used to screen the FDA-approved anti-cancer drugs. Those screens will include experiments in the presence of the osteosarcoma standard-of-care MAP chemotherapy as combined therapy with MAP is the most likely clinical application. Our preliminary results have identified multiple drugs that inhibit sarcosphere growth at doses that are safe for non-transformed cells.
Our Specific Aims are:
Aim 1 : Determine potential therapeutics that inhibit growth of 3D osteosarcoma tumor models at doses that are safe for non-transformed cells.
Aim 2 : Determine potential therapeutics that target osteosarcoma stemness.
Aim 3 : Determine potential therapeutics that inhibit growth of osteosarcoma metastases in vivo. OVERALL IMPACT: This project will identify promising new therapeutic options for osteosarcoma patients that can be rapidly translated to the clinic. Our screening strategy represents an innovative paradigm to rapidly identify novel therapeutics for osteosarcoma and could be extended to other sarcomas that also have poor clinical outcomes.
Osteosarcoma predominantly affects rapidly growing bones in children and adolescents and accounts for the majority of deaths from bone tumors, which are the third most common cause of cancer-related deaths in adolescents. Despite aggressive chemotherapeutic and surgical therapies, the survival rate is only 25% for patients who present with lung metastasis and 60-70% for those without detectable metastasis. Our goal is therefore to identify novel therapeutic agents that block the growth of lung metastases __ the lethal process in osteosarcoma.
