Tumor heterogeneity of gastric cancer: From the perspective of tumor-initiating cell

Table 2 Gastric tumor-initiating cell-targeted therapeutic strategies/agents

Therapeutic target	Therapeutic agent	Investigation status	Underlying mechanism	Treatment	Result of treatment	Ref.
ATOH1	Lentiviral vector-based	Preclinical investigation	Overexpression of ATOH1 mediates its transcriptional activity to downstream genes and induces the differentiation of GATICs	Lentiviral vector-based overexpression of ATOH1	(1) Induction of CD44+/Lgr5+ GATICs differentiation (2) Reduced tumorigenicity of GATICs both in vitro and in vivo	Han et al[115]
PGK1	Lentiviral vector-based	Preclinical investigation	Knockdown of PGK1 alters the glycolytic metabolism of GATICs not only induces GATIC differentiation but also improve their chemosensitivity	Lentiviral vector-based knockdown of PGK1	(1) Induction of CD44+ GATICs differentiation (2) Inhibited tumor growth and metastasis in vivo	Zieker et al[116]
CD44v	Sulfasalazine	Phase I dose-escalation clinical study in EPOC1205	Targeting CD44v by inhibiting xCT which mainly interacts with CD44v and maintains high level of GSH	12 g/d, 4x/d with 2 wk as one cycle, oral administration	Reduced level of CD44v positive GATICs in some patients	Shitara et al[130]
EpCam	Catumaxomab	Phase II/III clinical trial of advanced gastric carcinoma_NCT00836654	Direct targeting CD3 and EpCam	Paracentesis +/- Catumaxomab	Clinical benefit (prolonged PFS and less symptoms of ascites) in GC patients with secondary malignant ascites	Heiss et al[131]
EpCam	Catumaxomab	Phase II clinical trial of advanced gastric carcinoma_NCT01784900	Direct targeting CD3 and EpCam	Surgical resection followed by Catumaxomab	Intra-/postoperative administration of catumaxomab within multimodal treatment is feasible and tolerable	Goéré et al[132]
c-MET	Rilotumumab	Phase III clinical trial of locally advanced or metastatic gastric and GEJ carcinoma_NCT01697072	Competitively targeting hepatocyte growth factor (HGF), ligand of c-MET receptor	ECX +/- Rilotumumab	Stopped early due to increased death risk	Doshi et al[133]
c-MET	Onartuzumab	Phase III clinical trial of metastatic HER2(-) and c-MET(+) Gastroesophageal Cancer_NCT01662869	Direct targeting c-MET as a MET antagonist	FOLFOX6 +/- Rilotumumab	Insignificant prolong of PFS (6.9 mo vs 5.7 mo) and OS (11.0 mo vs 9.7 mo)	Shah et al[134]
c-MET	Tivantinib	Phase I/II clinical trial of advanced and metastatic adenocarcinoma of distal esophagus, GEJ and stomach_NCT01611857	Inhibition of c-Met receptor tyrosine kinase	FOLFOX6 combined with Tivantinib	PFS: 6.1 mo and OS: 9.6 mo	Pant et al[135]
SHH signaling pathway	Cyclopamine	Preclinical investigation	Targeting overexpressed Ptch/Gli1 (key effectors in SHH pathway)	Direct addition of cyclopamine (5 μmol/L in vitro and 10 μmol/L in vivo)	(1) Reduced self-renewing capacity of GATIC-enriched tumor sphere (2) Enhanced efficacy of Oxaliplatin/Mitomycin inhibiting proliferation of tumor sphere	Song et al[80]
SHH signaling pathway	Vismodegib	Phase II clinical trial of advanced gastric and GEJ carcinoma_NCT00982592	Targeting Smoothened (SMO) and its downstream GLI family members	FOLFOX +/- Vismodegib	(1) No significant improvement of anti-tumor activity (2) Potentially reverse the chemotherapy resistance of patients with high CD44-expressing tumor cells	Cohen et al[136]
Wnt/β-catenin signaling pathway	Salinomycin	Preclinical investigation	Blocking and degrading LRP6 (Wnt co-receptor)	Direct addition of Salinomycin (ranging from 1 μmol/L to 100 μmol/L in vitro)	Effectively kill ALDH-high GATICs which are resistant to 5-FU and CDDP	Mao et al[87]
Wnt/β-catenin signaling pathway	ICG-001	Preclinical investigation	Inhibiting CBP (co-activator of Wnt/β-catenin pathway)	Direct addition of ICG-001 (50 mg/kg/d, in vivo)	(1) Suppressed GC cell growth and metastasis both in vitro and in vivo (2) Reduced self-renewal capacity and enhanced efficacy of 5-Fu/cisplatin	Liu et al[122]
STAT3 signaling pathway	Napabucasin	Phase Ib/II dose-escalation and extension study of advanced gastric and GEJ carcinoma_NCT01325441	Direct targeting Stat3, β-catenin and NANOG	Paclitaxel +/- Napabucasin	(1) Well-tolerated by GC patients even receiving high doses of chemotherapy (2) Observed anti-tumor activity but still needs to be further confirmed in the on-going BRIGHTER phase III clinical trial	Shah et al[137]

GATIC: Gastric tumor-initiating cell; SHH: Sonic hedgehog; GEJ: Gastroesophageal junction; GC: Gastric cancer; ALDH: Aldehyde dehydrogenase.