title: Can pharmacogenomics help to improve therapy in patients with high-grade osteosarcoma?
abstract: Current standard treatment of patients with high-grade osteosarcoma (HGOS) includes complete surgical resection of the tumor and chemotherapy, most often with high-dose methotrexate, doxorubicin and cisplatin. With this approach > 60% of patients can be cured. However, conventional anticancer drugs have a narrow therapeutic index, and efficacy and toxicity vary considerably among patients. Pharmacogenomics aim to identify key genomic factors for drug effects (either desired or adverse) in normal host cells (germ-line variants) and cancer cells (somatic variants), and if an association between a genotype and a drug phenotype has been identified, validated and demonstrated to have a large effect size, these genotypes may be used to tailor therapy. In addition, pharmacogenomic models can be used to identify novel therapeutic targets. For example, germ-line variants in genes which potentially influence the disposition of methotrexate and cardiotoxicity of doxorubicin have recently been identified. Moreover, next-generation sequencing combined with several analytical methods has identified the phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway as a potential therapeutic target in HGOS. Herein, we discuss whether and how these novel pharmacogenomic insights may help to improve future therapy in HGOS.
authors.affiliation: St. Anna Children's Hospital, Department of Pediatrics, Medical University Vienna , Kinderspitalgasse 6, A-1090 Vienna , Austria +43 1 401702800 ; +43 1 401707280 ; leo.kager@stanna.at.
authors.forename: Leo
authors.initials: L
authors.lastname: Kager
authors.forename: Christopher
authors.initials: C
authors.lastname: Diakos
authors.forename: Stefan
authors.initials: S
authors.lastname: Bielack
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015195:Drug Design; D005838:Genotype; D006801:Humans; D058990:Molecular Targeted Therapy; D060787:Neoplasm Grading; D012516:Osteosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010597:Pharmacogenetics; D010641:Phenotype
chemical_list: D000970:Antineoplastic Agents
keywords: efficacy; osteosarcoma; pharmacogenomics; toxicity