Related Experiment Video
Updated: Jan 6, 2026
Utilizing Functional Genomics Screening to Identify Potentially Novel Drug Targets in Cancer Cell Spheroid Cultures
Published on: December 26, 2016
Screening FDA-Approved Oncology Drugs with Three-Dimensional Spheroids Identifies Romidepsin as a Therapeutic
Emily E Seiden1,2,3,4, Spencer M Richardson1,2, Leah A Everitt5
1Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, Indiana.
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.
Insights
Romidepsin, a histone deacetylase inhibitor, shows promise in treating metastatic osteosarcoma by targeting lung micrometastases. This drug is effective in patient-derived models and may help identify responsive individuals.
Area of Science:
- Oncology
- Pharmacology
- Biomedical Research
Background:
- Osteosarcoma is a common bone cancer with poor survival rates, especially with lung metastases.
- Current treatments have limited efficacy against micrometastases, necessitating new therapeutic strategies.
- Targeting micrometastases is crucial for improving osteosarcoma patient outcomes.
Purpose of the Study:
- To screen FDA-approved oncology drugs for efficacy against highly metastatic osteosarcoma.
- To identify novel therapeutic agents effective against lung micrometastases.
- To evaluate romidepsin's potential for repurposing in osteosarcoma treatment.
Main Methods:
- Utilized a three-dimensional multicellular osteosarcoma spheroid (sarcosphere) model to mimic in vivo micrometastases.
- Screened a panel of FDA-approved oncology drugs, including histone deacetylase inhibitors (HDIs).
- Assessed romidepsin's efficacy in combination with standard chemotherapy (MAP) and its effects on non-transformed cells.
Main Results:
- Romidepsin emerged as the most promising HDI, demonstrating potent anti-metastatic effects in sarcospheres at clinically achievable concentrations.
- Romidepsin showed efficacy both alone and with MAP chemotherapy, outperforming other HDIs.
- Patient-derived sarcospheres showed variable response to romidepsin, indicating potential for personalized treatment.
Conclusions:
- Romidepsin is a promising candidate for repurposing in human and canine metastatic osteosarcoma.
- Sarcosphere-based screening can identify romidepsin-sensitive and -resistant patients.
- This approach may guide clinical decisions for romidepsin therapy in osteosarcoma.
