Abstract
Osteosarcoma is the most common primary malignant bone tumor and predominantly affects adolescents and young adults. It is the third most common cause of cancer-related deaths among 9 to 24 year olds. Despite aggressive chemotherapeutic and surgical therapies, the survival rate is only 25% for patients with detectable lung metastases at diagnosis and only 70% in patients who present without detectable lung metastases. The poor prognosis is due to growth of metastases irrespective of whether they are initially large enough to detect clinically. It is therefore necessary to develop new methods to target the growth of lung micrometastases. An NCI panel of FDA-approved oncology drugs was therefore screened using three highly metastatic human osteosarcoma cell lines. To more closely approximate in vivo micrometastases, the screen used a three-dimensional multicellular in vitro osteosarcoma spheroid (sarcosphere) model. Among 13 hits from the initial screen, we identified the histone deacetylase inhibitor (HDI) romidepsin as the most promising inhibitor in secondary screens comparing effects on sarcospheres with clinically achievable levels and to effects on non-transformed cells. Romidepsin potency was evident with and without standard-of-care chemotherapeutics (MAP: methotrexate, adriamycin, and cisplatin) at romidepsin concentrations that are clinically achievable and did not affect non-transformed cells. Romidepsin also substantially outperformed the other three FDA-approved HDIs and eight HDIs in clinical trials. The effects of romidepsin were a transient cell cycle block at G2/M and cell death. Importantly, sarcospheres derived from ∼30% of human and 50% of canine patient samples responded to romidepsin at clinically tolerable concentrations (ED50s <70 nmol/L). Significance: Our unbiased sarcosphere-based drug screen identified romidepsin as a promising candidate to repurpose for human and canine patients with metastatic osteosarcoma. This screening strategy allowed us to identify romidepsin-sensitive and -resistant patients. Sarcosphere-based screening may therefore be useful to identify patients most likely to respond clinically to romidepsin or other drugs.