Drug Repurposing as a Source of Innovative Therapies in Osteosarcoma
Chemotherapy and surgery achieve a 5-year event-free survival of 60-70% in localized osteosarcoma (OS), but little additional progress has been made in recent decades. Clinical research in OS is hampered by a limited pipeline of new agents. Drug repurposing, an alternative development pathway that seeks to reuse existing drugs as the source of new treatment options, represents an interesting opportunity to solve this issue. Repurposing benefits from existing data on safety, dosing and clinical experience.
Our goal was to list existing non-cancer drugs active against OS to prioritize future research and trials.
We used the Repurposing Drugs in Oncology (ReDO) list of 240 approved non-cancer drugs. We queried PubMed for each drug and screened all abstracts to assess relevance, type of evidence (in vitro, in vivo, human data) and mechanism(s) of action (MoA).
From the 240 drugs, 65 (27%) have evidence of activity against OS. Of these, 10 (15%) are supported by human data. We found certain MoA patterns and grouped drugs in 7 categories.
- Drugs affecting coagulation, adhesion and chemotaxis: aspirin, heparin, warfarin, plerixafor, disulfiram
- Epigenetic drugs: histone deacetylase inhibitors, DNA methyltransferase inhibitors
- Immunomodulators: all-trans retinoid acid (ATRA), thalidomide, sirolimus
- Differentiating agents: calcitriol, ATRA
- Drugs targeting osteosarcoma stem cells: plerixafor, metformin, disulfiram
- Chemo-potentiating drugs: caffeine, proton pump inhibitors, verapamil, piroxicam
- Direct cytotoxicity drugs: simvastatin, glucocorticoids
65 FDA-approved drugs have shown activity against OS. In terms of clinical setting, cytototoxic, epigenetic, differentiating and chemo-potentiating drugs could be tested in the neoadjuvant period to enhance the effect of chemotherapy. Immunomodulators and drugs affecting coagulation and chemotaxis could be tested during the perioperative period to prevent early recurrences. Based on our results, we are exploring the possibility of conducting international collaborative multi-arm trials to accelerate progress in OS.