Targeting the Insulin-Like Growth Factor 1 Receptor in Ewing's Sarcoma: Reality and Expectations

Table 1

IGF pathway targeting strategies in development.

Name	Class	Route	Company	Phase	Remarks in Ewing sarcomas	References
Anti-IGF 1-receptor monoclonal antibodies
AVE1642	Humanized IgG1	IV	Sanofi-Aventis	I-II	(i) Nil.	[65]
SCH-717454	Fully human IgG1	IV	Schering Plough	II	(i) PRs seen in EWS patients.; (ii) Phase II in relapsed EWS or osteosarcoma.	[66]
CP-751,871 figitumumab	Fully human IgG2	IV	Pfizer	II-III	(i) CR and PR in 2 pts with EWS. Prolonged SD in patients with EWS, synovial sarcoma and fibrosarcoma.; (ii) Phase II trial in refractory paediatric and adult EWS: 15 PRs and 21 SD by RECIST.	[67, 68]
IMC-A12 cixutumumab	Fully human IgG1	IV	ImClone systems	I-II	(i) Preclinical activity in EWS models.; (ii) Phase II with 5 tiers: one for EWS.	[69, 70]
BIIB022	Fully human IgG4	IV	Biogen Idec	I	(i) Phase I dose-escalation ongoing in all solid tumors, no EWS enrolled yet.	[71]
MK-0646	Humanized IgG1	IV	Merck	II	(i) Phase I dose-escalation studies completed.; (ii) SD in 2 patients: EWS and DSRCT respectively.	[69, 72]
R1507 Robatumumab	Fully human IgG1	IV	Hoffman-La Roche	II	(i) Several PRs and prolonged SD in pts with EWS.; (ii) Phase II in multiple sarcoma subtypes halted since 12/22/2009.	[73, 74]
AMG-479	Fully human IgG1	IV	Amgen	II	(i) CR and PR in 2 EWS patients.; (ii) Phase II in relapsed Ewing and DSRCT. In EWS 1 PR and 1 SD >6 months.	[75, 76]
Anti-IGF-1-receptor small molecule/tyrosine kinase Inhibitors
INSM-18	Small molecule TKI	PO	Insmed	I-II	(i) An ATP competitive and reversible TKI, which also inhibits HER2.
BMS-754807	Small molecule TKI	PO	Bristol Myers Squibb	I	(i) An ATP competitive and reversible TKI.; (ii) In vitro activity against in EWS, RMS, liposarcoma cell lines.	[52]
OSI-906	Small molecule TKI	PO	OSI pharmaceuticals	I	(i) An ATP competitive and reversible TKI.; (ii) Phase I enrolled 2 Ewing sarcoma patients without benefit.	[77]
XL-228	Small molecule TKI	IV	Exelixis	I	(i) An ATP competitive TKI of IGF-1R, Aurora, FGFR and Src.; (ii) Prolonged SD in 2 pts with leiomyosarcoma (≥7 m) and liposarcoma (≥5 m) respectively.	[78]
BVP-51004 cyclolignan, PPP	Small molecule TKI	PO	Biovitrum	I	(i) A non-ATP competitive TKI.; (ii) In vitro activity in multiple sarcoma resistant cell lines, including osteosarcoma.	[79]
A-947864	Small molecule TKI	PO	Abbott	Preclinical	(i) An ATP competitive TKI.
BMS-554417	Small molecule TKI	PO	Bristol Myers Squibb	Preclinical	(i) An ATP-competitive and reversible TKI.; (ii) In vitro activity in EWS and osteosarcoma cell lines.	[80]
NVP-AEW541 NVP-ADW742	Small molecule TKIs	PO	Novartis	Preclinical	(i) ATP competitive and reversible TKIs.; (ii) In vitro and in vivo activity in EWS.	[51, 53]
GSK1904529A GSK1838705A	Small molecule TKIs	PO	GlaxoSmithKline	Preclinical	(i) ATP-competitive, reversible, TKIs of IGF-1R and IR.; (ii) In vitro activity in EWS cell lines.	[50, 81]
AG1024 (Tyrphostin)	Small molecule TKI	N.A.	Merck	Preclinical	(i) Used mainly in preclinical drug testing, Non-ATP competitive.

Ref: reference; IgG: immunoglobulin G; SD: stable disease; PR: partial response; CR: complete response; pt: patient; EWS: Ewing sarcoma; ESFTs: Ewing sarcoma family of tumors; RMS: rhabdomyosarcoma; DSRCT: desmoplastic small round cell tumor; TKI: tyrosine kinase inhibitor; m: months.