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Updated: Nov 5, 2025
Author Spotlight: Exploring Advanced Therapeutic Targets in Osteosarcoma Through Spatial Transcriptomics
Published on: May 3, 2024
New drug candidates for osteosarcoma: Drug repurposing based on gene expression signature
Raissa Coelho Andrade1, Mariana Boroni2, Marion Kielmanowicz Amazonas3
1Birth Defects Epidemiology Laboratory, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil; Genetics and Molecular Biology Department, Federal University of the State of Rio de Janeiro (UNIRIO), Rio de Janeiro, Brazil.
Abstract:
Osteosarcoma (OS) is an aggressive bone malignancy and the third most common cancer in adolescence. Since the late 1970s, OS therapy and prognosis had only modest improvements, making it appealing to explore new tools that could help ameliorate the treatment. We present a meta-analysis of the gene expression signature of primary OS, and propose small molecules that could reverse this signature. The meta-analysis was performed using GEO microarray series. We first compared gene expression from eleven primary OS against osteoblasts to obtain the differentially expressed genes (DEGs). We later filtered those DEGs by verifying which ones had a concordant direction of differential expression in a validation group of 82 OS samples versus 30 bone marrow mesenchymal stem cells (BM-MSC) samples. A final gene expression signature of 266 genes (98 up and 168 down regulated) was obtained. The L1000CDS2 engine was used for drug repurposing. The top molecules predicted to reverse the signature were afatinib (PubChem CID 10184653), BRD-K95196255 (PubChem CID 3242434), DG-041 (PubChem CID 11296282) and CA-074 Me (PubChem CID 23760717). Afatinib (Gilotrif™) is currently used for metastatic non-small-cell lung cancer with EGFR mutations, and in vitro evidence shows antineoplastic potential in OS cells. The other three molecules have reports of antineoplastic effects, but are not currently FDA-approved. Further studies are necessary to establish the potential of these drugs in OS treatment. We believe our results can be an important contribution for the investigation of new therapeutic genetic targets and for selecting new drugs to be tested for OS.
Insights
This study identified a 266-gene signature in osteosarcoma (OS) and proposed small molecules, including afatinib, to reverse it. These findings may guide new therapeutic targets and drug development for this aggressive bone cancer.
Area of Science:
- Oncology
- Genomics
- Pharmacology
Background:
- Osteosarcoma (OS) is an aggressive bone cancer with limited therapeutic advancements.
- Novel therapeutic strategies are crucial for improving OS patient prognosis.
Purpose of the Study:
- To identify a gene expression signature in primary osteosarcoma.
- To propose small molecules capable of reversing the identified OS gene signature.
Main Methods:
- Meta-analysis of gene expression data from GEO microarray series.
- Differential gene expression analysis comparing OS samples with osteoblasts and mesenchymal stem cells.
- Drug repurposing using the L1000CDS2 engine.
Main Results:
- A distinct gene expression signature of 266 genes (98 upregulated, 168 downregulated) was identified in osteosarcoma.
- Afatinib, BRD-K95196255, DG-041, and CA-074 Me were predicted to reverse the OS signature.
- Afatinib demonstrated in vitro antineoplastic potential in OS cells.
Conclusions:
- The identified gene signature provides a basis for understanding OS molecular mechanisms.
- The proposed small molecules represent potential candidates for novel osteosarcoma therapies.
- Further clinical investigation is warranted to validate these findings for osteosarcoma treatment.
