title: Ewing sarcoma: The clinical relevance of the insulin-like growth factor 1 and the poly-ADP-ribose-polymerase pathway.
abstract: BACKGROUND
  In the last three decades the outcome for patients with localised Ewing sarcoma (ES) has improved significantly since the introduction of multimodality primary treatment. However, for patients with (extra-) pulmonary metastatic and/or non-resectable relapsed disease the outcome remains poor and new treatment options are urgently needed. Currently the insulin-like growth factor 1 receptor (IGF-1R) pathway and the poly-ADP(adenosinediphosphate)-ribose-polymerase (PARP) pathway are being investigated for potential targeted therapies. IGF-1R: The IGF-1R pathway is known to be deregulated by the EWSR1-FLI1 translocation which makes it a potential target for therapy. Clinical trials have been reported in which only ES patients were treated with an IGF-1R inhibitor, either as single agent or in combination. In total 291 ES patients were included in these trials, in which two (0.7%) complete responses, 32 (11%) partial responses of which some durable, and 61 (21%) stable diseases were observed. PARP: In the presence of a PARP inhibitor DNA strand breaks cannot be efficiently repaired, leading to cell death. The first phase II trial with ES patients was recently published and showed no clinical responses, which may have been due to the drug being non-effective as a single agent.
  
  
  CONCLUSIONS
  The IGF-1R pathway is an interesting target for ES and should be explored further, as biomarkers to select patients that might benefit from treatment are lacking. PARP inhibitors as single agent have so far failed to show improvement in outcome. Future directions include dual insulin receptor/IGF-1R blockade with linsitinib as well as chemotherapy-PARP combinations. Both therapeutic strategies are currently being explored.
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Centre, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. Electronic address: a.m.van_maldegem@lumc.nl.
authors.forename: Annemiek M
authors.initials: AM
authors.lastname: van Maldegem
authors.affiliation: Department of Pathology, Leiden University Medical Centre, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. Electronic address: j.v.m.g.bovee@lumc.nl.
authors.forename: Judith V M G
authors.initials: JV
authors.lastname: Bovée
authors.affiliation: Department of Pathology, Leiden University Medical Centre, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. Electronic address: e.f.p.peterse@lumc.nl.
authors.forename: Elleke F P
authors.initials: EF
authors.lastname: Peterse
authors.affiliation: Department of Pathology, Leiden University Medical Centre, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. Electronic address: p.c.w.hogendoorn@lumc.nl.
authors.forename: Pancras C W
authors.initials: PC
authors.lastname: Hogendoorn
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Centre, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. Electronic address: a.j.gelderblom@lumc.nl.
authors.forename: Hans
authors.initials: H
authors.lastname: Gelderblom
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D017209:Apoptosis / Q000502:physiology; D001859:Bone Neoplasms / Q000378:metabolism / Q000628:therapy*; D002986:Clinical Trials as Topic; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000627:therapeutic use; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012512:Sarcoma, Ewing / Q000378:metabolism / Q000628:therapy*; D015398:Signal Transduction
chemical_list: D000911:Antibodies, Monoclonal; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D007334:Insulin-Like Growth Factor I; D011065:Poly(ADP-ribose) Polymerases; D017526:Receptor, IGF Type 1
keywords: Bone tumour; Ewing sarcoma; IGF-1R; PARP pathway; Sarcoma; Soft tissue tumour