Table 1: Molecular targets according to malignant characteristics and current development of targeted therapies in osteosarcomas and Ewing sarcomas.

Targets Agents Clinical development in different tumour typesOsteosarcomaEwing sarcoma

EWS-FLI1 inhibitionAntisense oligonucleotide, antisense RNA, siRNA P
MithramycinI ped/II ad ongoing, NCT01610570
YK-4-279P
ET-743 (trabectedin; Yondelis*)I ped/II adI ped/II ped

Cell growth Inhibition
 GFR inhibitors
  IGFR inhibitorsR1507; SCH 717454; CP-751871; IMC-A12I pedII ped (EW: 10–15% objective response rate)
   mTOR inhibitorsEverolimus (RAD001, Afinitor*)I/II pedI ped
Temsirolimus (Torisel*)I/II pedI/II ped
Ridaforolimus I ped ongoing, NCT01431547 all solid tumoursII/III ad II/III ad
  CombinationEWS-FLI1 antisense oligonucleotide + mTOR inhibitor/P
Rapamycin + irinotecan (RAPIRI)I ped ongoing, NCT01282697 all solid tumoursPP
Cixutumumab + temsirolimusII ped/II ad ongoing (NCT01614795)/ II ped/II ad ongoing (NCT01614795)
Ridaforolimus + dalotuzumabI ped ongoing, NCT01431547 all solid tumoursI ped/
 Multitarget inhibitorsImatinib mesylate, Glivec* (PDFGR, c-KIT, BCR-ABL)PII ped
Imatinib + ifosfamideI ped/
Dasatinib, Sprycel* (Src, BCR-ABL)PI ped
 Cell cycle inhibitors CDK inhibitors SCH 727965 (dinaciclib)I ad/
Rexin-G/
Aurora A inhibitorsP
MLN8237I/II ped ongoing, NCT01154816/NCT00739427P
Solid tumours or leukemiaP
AT9283I ped ongoing, NCT00985868/NCT01431664P
Solid tumours/leukemiaP
PLK1 inhibitor, BI 2536P/
MDM2 inhibitors, nutlin-3I ad ongoing, NCT01462175 solid tumoursP

Angiogenesis inhibitionSorafenib, Nexavar* (Raf, c-KIT, PDGFR, VEGF) II adI ped ongoing, NCT01518413
Sunitinib, Sutent* (Flt3, c-KIT, PDGFR, VEGF) I ped I ped
Pazopanib (VEGFR1–3, PDGFRα/β, c-Kit)P I ped
Pazopanib + topotecanI ped ongoing, NCT00326664 CNS tumoursP P
Pazopanib + everolimusI ad ongoing, NCT01430572 solid tumours//
Cediranib, AZD2171 (VEGFR)III ped/adI ped
Bevacizumab Avastin*  NCT00667342 trial I/II pedI/II ped
Bevacizumab + vincristine/topotecan/cyclophosphamide/II ped ongoing, NCT00516295
III ped/ad ongoing, NCT00667342/
Bevacizumab + CT1st-line randomised study, combination CT

Resistance to cell death
  Apoptosis BCL2 inhibitors, navitoclax (ABT-263)/P
TRAIL inhibitorsPP
SMAC mimetic, LCL161I ad ongoing, NCT01098838 solid tumoursPP
PARP inhibitors/P
  AutophagyAntisense oligonucleotide of X-linked IAP PP
  Telomerase activityTelomerase inhibitor, TMPyP4PP

Inhibition of metastatic phenotype
  InvasionGamma secretase (NOCTH Inhibitors), MK-0752I ad/ped leukemiaP P
  MigrationMET/ALK inhibitors (Crizotinib)II ped >15 y ongoing, NCT00939770, solid tumoursP/
  Resistance to anoikisGSK3beta inhibitors (Wnt pathway activation)I ad ongoing, NCT01457417, NCT00741377 myelomaP /
  ChemotactismCXCR4 inhibitors (plerixafor)I ped ongoing, NCT01319864 leukemia/MDSP P
  Adhesion Integrin inhibitors, cilengitide EMD121974I ped ongoing, NCT01165333 CNSP /

Modulation antitumour immune responseINFαIII ped/ad (EURAMOS I trial, results awaited)/
1st-line randomised study, combination CT
L-MTP-PE, mifamurtide MEPACT*III ped/ad (INT-0133 trial closed) /
Inhaled sargramostim (rhGM-CSF) II ad ongoing, NCT00066365: Pulmonary relapses/
Celecoxib, COX2 inhibitors/P
Anti-GD2 antibodies (ch14.18)I/II ped, neuroblastomaI pedP

Bone microenvironmentIII ped/ad OS2006 trial ongoing, NCT00470223III ped/ad protocol ewing 2008 and EE2012
Zoledronic acid, Zometa*1st-line randomised study, combination CT 1st-line randomised study, combination CT
For localised EW + good histological response
Denosumab (Ac anti-RANKL)II ad/ped >12 ans ongoing, NCT00680992 GCTPP
SamariumII ad/

Other pathways
  Hedgehog inhibitors Smo inhibitor LDE225 (ongoing)I ped ongoing, NCT01125800 solid tumoursP/I ped, NCT01125800 P
  HDAC inhibitorsVorinostat, valproic acid, FK228P/I pedI ped
  HSP90 inhibitors17-AAG I pedI ped

CNS: central nervous system; GFR: growth factor receptor; P: preclinical studies; I: phase Itrial; II: phase IItrial; III: phase IIItrial; ped: paediatric; ad: adult; CT: chemotherapy; CGT: giant cell tumour.