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Repurposing Romidepsin for Osteosarcoma: Screening FDA-Approved Oncology Drugs with Three-Dimensional Osteosarcoma
Abstract:
Osteosarcoma is the most common primary malignant bone tumor and predominantly affects children, adolescents, and young adults. It is the third most common cause of cancer-related deaths among 9-24-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 that 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 micro-metastases, the screen used a 3D 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 based on sarcosphere viability. Romidepsin potency was evident with and without standard-of-care chemotherapeutics (MAP: Methotrexate, Adriamycin, Cisplatin) at drug concentrations that are clinically achievable and did not affect non-transformed cells. By those criteria, romidepsin also substantially outperformed the other three FDA-approved HDIs and eight HDIs in clinical trials. Importantly, sarcospheres derived from 30-50% of human and canine patient samples were also sensitive to romidepsin with ED50s 10- to 700-fold less than the Cmax in human patients. Based on these 3-D screening approaches, romidepsin is a promising drug to repurpose for osteosarcoma.
Significance Statement:
Our unbiased sarcosphere-based drug screen identified romidepsin as a promising candidate to repurpose for canine and human patients with metastatic osteosarcoma. This screening strategy allowed us to identify romidepsin-sensitive and -resistant patients. Sarcosphere-based screening may therefore be useful to stratify patients most likely to respond clinically to romidepsin or other drugs.
Insights
Romidepsin shows promise for treating osteosarcoma lung micrometastases. This histone deacetylase inhibitor is effective in 3D models and patient samples, potentially improving survival rates for this common bone cancer.
Area of Science:
- Oncology
- Pharmacology
- Biotechnology
Background:
- Osteosarcoma is the most common primary malignant bone tumor, with poor survival rates, especially when lung metastases are present.
- Existing therapies have limited efficacy against micrometastases, necessitating novel treatment strategies.
- Targeting the growth of lung micrometastases is crucial for improving patient outcomes in osteosarcoma.
Purpose of the Study:
- To screen FDA-approved oncology drugs for efficacy against highly metastatic human osteosarcoma cell lines.
- To identify novel therapeutic agents capable of inhibiting the growth of osteosarcoma micrometastases.
- To evaluate romidepsin as a potential repurposed drug for osteosarcoma treatment.
Main Methods:
- A 3D multicellular in vitro osteosarcoma spheroid (sarcosphere) model was utilized to simulate in vivo micrometastases.
- An NCI panel of FDA-approved oncology drugs was screened using three highly metastatic human osteosarcoma cell lines.
- Romidepsin's efficacy was assessed based on sarcosphere viability, both alone and in combination with standard chemotherapeutics (MAP).
Main Results:
- Romidepsin was identified as the most promising inhibitor among 13 initial hits, demonstrating potent anti-cancer activity in sarcosphere viability assays.
- The drug showed efficacy at clinically achievable concentrations without affecting non-transformed cells and outperformed other histone deacetylase inhibitors.
- Sarcospheres from human and canine patient samples exhibited sensitivity to romidepsin, indicating its potential clinical relevance.
Conclusions:
- Romidepsin is a promising candidate for repurposing in the treatment of metastatic osteosarcoma in both human and canine patients.
- The sarcosphere-based screening approach effectively identified romidepsin-sensitive and -resistant patient populations.
- This screening strategy may aid in stratifying patients likely to respond to romidepsin or other therapeutic agents.
