Bone Sarcomas: From Biology to Targeted Therapies

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 types	Osteosarcoma	Ewing sarcoma
EWS-FLI1 inhibition	Antisense oligonucleotide, antisense RNA, siRNA			P
	Mithramycin			I ped/II ad ongoing, NCT01610570
	YK-4-279			P
	ET-743 (trabectedin; Yondelis*)		I ped/II ad	I ped/II ped
Cell growth Inhibition
GFR inhibitors
IGFR inhibitors	R1507; SCH 717454; CP-751871; IMC-A12		I ped	II ped (EW: 10–15% objective response rate)
mTOR inhibitors	Everolimus (RAD001, Afinitor*)		I/II ped	I ped
	Temsirolimus (Torisel*)		I/II ped	I/II ped
	Ridaforolimus	I ped ongoing, NCT01431547 all solid tumours	II/III ad	II/III ad
Combination	EWS-FLI1 antisense oligonucleotide + mTOR inhibitor		/	P
	Rapamycin + irinotecan (RAPIRI)	I ped ongoing, NCT01282697 all solid tumours	P	P
	Cixutumumab + temsirolimus		II ped/II ad ongoing (NCT01614795)/	II ped/II ad ongoing (NCT01614795)
	Ridaforolimus + dalotuzumab	I ped ongoing, NCT01431547 all solid tumours	I ped	/
Multitarget inhibitors	Imatinib mesylate, Glivec* (PDFGR, c-KIT, BCR-ABL)		P	II ped
	Imatinib + ifosfamide		I ped	/
	Dasatinib, Sprycel* (Src, BCR-ABL)		P	I ped
Cell cycle inhibitors	CDK inhibitors SCH 727965 (dinaciclib)		I ad	/
	Rexin-G			/
	Aurora A inhibitors		P
	MLN8237	I/II ped ongoing, NCT01154816/NCT00739427		P
		Solid tumours or leukemia	P
	AT9283	I ped ongoing, NCT00985868/NCT01431664		P
		Solid tumours/leukemia	P
	PLK1 inhibitor, BI 2536		P	/
	MDM2 inhibitors, nutlin-3	I ad ongoing, NCT01462175 solid tumours		P
Angiogenesis inhibition	Sorafenib, Nexavar* (Raf, c-KIT, PDGFR, VEGF)		II ad	I 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 + topotecan	I ped ongoing, NCT00326664 CNS tumours	P	P
	Pazopanib + everolimus	I ad ongoing, NCT01430572 solid tumours	/	/
	Cediranib, AZD2171 (VEGFR)		III ped/ad	I ped
	Bevacizumab Avastin*  NCT00667342 trial		I/II ped	I/II ped
	Bevacizumab + vincristine/topotecan/cyclophosphamide		/	II ped ongoing, NCT00516295
			III ped/ad ongoing, NCT00667342	/
	Bevacizumab + CT		1st-line randomised study, combination CT
Resistance to cell death
Apoptosis	BCL2 inhibitors, navitoclax (ABT-263)		/	P
	TRAIL inhibitors		P	P
	SMAC mimetic, LCL161	I ad ongoing, NCT01098838 solid tumours	P	P
	PARP inhibitors		/	P
Autophagy	Antisense oligonucleotide of X-linked IAP		P	P
Telomerase activity	Telomerase inhibitor, TMPyP4		P	P
Inhibition of metastatic phenotype
Invasion	Gamma secretase (NOCTH Inhibitors), MK-0752	I ad/ped leukemia	P	P
Migration	MET/ALK inhibitors (Crizotinib)	II ped >15 y ongoing, NCT00939770, solid tumours	P	/
Resistance to anoikis	GSK3beta inhibitors (Wnt pathway activation)	I ad ongoing, NCT01457417, NCT00741377 myeloma	P	/
Chemotactism	CXCR4 inhibitors (plerixafor)	I ped ongoing, NCT01319864 leukemia/MDS	P	P
Adhesion	Integrin inhibitors, cilengitide EMD121974	I ped ongoing, NCT01165333 CNS	P	/
Modulation antitumour immune response	INFα		III 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, neuroblastoma	I ped	P
Bone microenvironment			III ped/ad OS2006 trial ongoing, NCT00470223	III 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 GCT	P	P
	Samarium		II ad	/
Other pathways
Hedgehog inhibitors	Smo inhibitor LDE225 (ongoing)	I ped ongoing, NCT01125800 solid tumours	P/I ped, NCT01125800	P
HDAC inhibitors	Vorinostat, valproic acid, FK228		P/I ped	I ped
HSP90 inhibitors	17-AAG		I ped	I 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.