title: The biology and management of cartilaginous tumors: a role for targeting isocitrate dehydrogenase.
abstract: Chondrosarcomas are rare mesenchymal neoplasms defined by the production of abnormal cartilaginous matrix. Conventional chondrosarcoma is the most common histology. The management of primary conventional chondrosarcoma generally is surgical with the possible addition of radiation therapy. Treatment of conventional chondrosarcoma is problematic in unresectable or metastatic disease because the tumors tend to be resistant to standard sarcoma chemotherapy regimens. Previous attempts at targeted therapy, including inhibitors of Hedgehog signaling, the mTOR pathway, and platelet-derived growth factor receptor (PDGFR) have been largely disappointing. However, heterozygous mutations in isocitrate dehydrogenase (IDH) enzymes recently have been identified in chondrogenic neoplasms, with mutations reported in approximately 87% of benign enchondromas, 70% of conventional chondrosarcomas, and 54% of dedifferentiated chondrosarcomas. The normal IDH protein continues to produce alpha-ketoglutarate (alpha-KG) whereas the mutant IDH protein converts KG to the oncometabolite 2-hydroxyglutarate (2-HG). Clinical trials of novel IDH inhibitors are ongoing, with evidence of early activity in IDH-mutant leukemias. IDH inhibitors show antitumor effects against IDH-mutant chondrosarcoma cell lines, supporting the inclusion of patients with chondrosarcoma with IDH mutations on IDH inhibitor clinical trials for solid tumors. Targeting IDH mutations may offer hope of a novel antineoplastic strategy not only for patients with chondrosarcomas, but also for other solid tumors with aberrant IDH activity.
authors.affiliation: From the Sylvester Comprehensive Cancer Center, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL; Sylvester Comprehensive Cancer Center, Department of Pathology, University of Miami Miller School of Medicine, Miami, FL.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Tinoco
authors.affiliation: From the Sylvester Comprehensive Cancer Center, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL; Sylvester Comprehensive Cancer Center, Department of Pathology, University of Miami Miller School of Medicine, Miami, FL.
authors.forename: Breelyn A
authors.initials: BA
authors.lastname: Wilky
authors.affiliation: From the Sylvester Comprehensive Cancer Center, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL; Sylvester Comprehensive Cancer Center, Department of Pathology, University of Miami Miller School of Medicine, Miami, FL.
authors.forename: Ana
authors.initials: A
authors.lastname: Paz-Mejia
authors.affiliation: From the Sylvester Comprehensive Cancer Center, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL; Sylvester Comprehensive Cancer Center, Department of Pathology, University of Miami Miller School of Medicine, Miami, FL.
authors.forename: Andrew
authors.initials: A
authors.lastname: Rosenberg
authors.affiliation: From the Sylvester Comprehensive Cancer Center, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL; Sylvester Comprehensive Cancer Center, Department of Pathology, University of Miami Miller School of Medicine, Miami, FL.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Trent
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000145:classification / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D002813:Chondrosarcoma / Q000145:classification / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000235:genetics; D058990:Molecular Targeted Therapy / Q000379:methods; D009154:Mutation
chemical_list: D000970:Antineoplastic Agents; D007521:Isocitrate Dehydrogenase