Therapeutic targets in gastrointestinal stromal tumors

Table 1 Risk stratification of primary gastrointestinal stromal tumor by mitotic index, size and anatomic location[2]

Prognosis of primary GIST
Risk	Size (cm)	Mitotic count (per 50 HPF)
Very low risk	< 2	< 5
Low risk	2-5	< 5
Intermediate risk	< 5	6-10
	5-10	< 5
High risk	> 5	> 5
	> 10	> Any mitotic rate
	Any tumor	> 10

HPF: High power fields; GIST: Gastrointestinal stromal tumor.

Table 2 Novel agents are being developed for gastrointestinal stromal tumor therapy[10,13,14,21,30,64,67-84]

Agent	Molecular target	Phase
Kinase inhibitors
Nilotinib	KIT, PDGFRs, BCR-ABL	I
Sorafenib	Raf, KIT, PDGFRB, VEGFR, FLT3, RET	71%
Dasatinib	Src, ABL, KIT, PDGFRs	Phase II ongoing in advanced sarcomas and accepting patients
Cediranib (AZD2171)	VEGFR, KIT, PDGFRs	Phase II ongoing
OSI-930	VEGFR, KIT	Phase II ongoing, not recruiting
Linsitinib (OSI-906 )	IGF1R	Phase III
Vatalanib (PTK787)	VEGFR, KIT, PDGFRs	67%
Motesanib (AMG706)	VEGFR, KIT, PDGFRs, RET	24%-27%
XL820	KIT, PDGFRB, VEGFR	Phase II ongoing, not recruiting
mTOR and AKT inhibitors
Perifosine	AKT	Phase II ongoing in combination with imatinib
Everolimus	mTOR	26%
Temsirolimus	mTOR	Phase II ongoing, closed recruitment
Hsp90 inhibitors
17-AAG	Hsp90	Phase II/III
Ganetespib (STA-9090)	Hsp90	Phase II
AUY922	Hsp90	Phase II
AT13387	Hsp90	Phase II ongoing in combination with imatinib
IPI-504	Hsp90	78%, phase III ended due to safety concerns
Others
Flavopiridol	Transcription inhibitor	Phase I ongoing in combination with doxorubicin
Clinical benefit is defined as complete or partial response or stable disease

PDGFRs: Platelet-derived growth factor receptors; PDGFRA: Platelet-derived growth factor receptor α; PDGFRB: Platelet-derived growth factor receptor β; VEGFR: Vascular endothelial growth factor receptor; FLT3: FMS-Like Tyrosine Kinase 3; IGF1R: Insulin-like growth factor 1 receptor; AKT: Protein kinase B; mTOR: Mammalian target of rapamycin; Hsp90: Heat shock protein 90; RET: Orphan receptor tyrosine kinase.