Potential target identification for osteosarcoma treatment: Gene expression re-analysis and drug repurposing

• Published in: Gene Vol. 856; p. 147106
• Main Authors: Kamolphiwong, Rawikant, Kanokwiroon, Kanyanatt, Wongrin, Weerinrada, Chaiyawat, Parunya, Klangjorhor, Jeerawan, Settakorn, Jongkolnee, Teeyakasem, Pimpisa, Sangphukieo, Apiwat, Pruksakorn, Dumnoensun
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 10.03.2023
• Subjects: Bone Neoplasms - drug therapy; Bone Neoplasms - genetics; Drug Repositioning; Drug repurposing; Gene expression; Gene Expression Profiling; Humans; KLHL13; Metastasis; Osteosarcoma; Osteosarcoma - drug therapy; Osteosarcoma - genetics; Transcriptome; SCG-PM; SCLC; FDA; DGE; SCG-PP; Drug repurposing; SCG-KP; HG-U133A; Metastasis; KLHL13; SCG-KM; Gene expression; GEO; SCG-TFP; PANTHER; PCG-P; PCG-M; Osteosarcoma; KEGG; SCG-TFM; HG-U133 plus 2; Hugene-1.0
• ISSN: 0378-1119; 1879-0038
• DOI: 10.1016/j.gene.2022.147106

[Display omitted] •KLHL13 is a new potential target for osteosarcoma based on re-analysis gene expression profile.•Datamining from microarrays identified 50 anti-cancer drugs from 29 targets has a potentiality for rapid application in clinical practice for osteosarcoma treatment (especially CDK4, BCL-2, JUN, SRC, PIK3CA).•Niclosamide and synthetic PPARɣ ligands are possible to be performed dose and efficacy optimization, or delivery modification for osteosarcoma treatment. Survival rate of osteosarcoma has remained plateaued for the past three decades. New treatment is needed to improve survival rate. Drug repurposing, a method to identify new indications of previous drugs, which saves time and cost compared to the de novo drug discovery. Data mining from gene expression profile was carried out and new potential targets were identified by using drug repurposing strategy. Selected data were newly categorized as pathophysiology and metastasis groups. Data were normalized and calculated the differential gene expression. Genes with log fold change ≥ 2 and adjusted p-value ≤ 0.05 were selected as primary candidate genes (PCGs). PCGs were further enriched to determine the secondary candidate genes (SCGs) by protein interaction analysis, upstream transcription factor and related-protein kinase identification. PCGs and SCGs were further matched with gene targeted of corresponding drugs from the Drug Repurposing Hub. A total of 778 targets were identified (360 from PCGs, and 418 from SCGs). This newly identified KLHL13 is a new candidate target based on its molecular function. KLHL13 was upregulated in clinical samples. We found 256 drugs from matching processes (50anti-cancerand206non-anticancerdrugs). Clinical trials of anti-cancer drugs from 5 targets (CDK4, BCL-2, JUN, SRC, PIK3CA) are being performed for osteosarcoma treatment. Niclosamide and synthetic PPARɣ ligands are candidates for repurposing due to the possibility based on their mechanism and pharmacology properties. Re-analysis of gene expression profile could identify new potential targets, confirm a current implication, and expand the chance of repurposing drugs for osteosarcoma treatment.