Table 1.

Strategies, pathways, and targets for eradicating CML stem cells

Pathway/target	Drug or agent	Mechanism of action or strategy	Clinical trials	Reference(s)
Signaling pathways
JAK2	Ruxolitinib	JAK2 inhibitor	NCT01702064, NCT01751425	49
PI3K/AKT/mTOR	Everolimus, temsirolimus	mTOR inhibitors	NCT01188889, NCT00093639, NCT00101088	60,61,64
WNT/β-catenin	Indomethacin	COX inhibitor		69
	SB216763	GSK-3βinhibitor		74
	CGP57380	MNK inhibitor		140
Hh pathway*	LDE225, PF-04449913, BMS-833923	Smo antagonists	NCT01456676, NCT00953758, NCT01218477	77–79
ALOX5 pathway	Zileuton	5-LO inhibitor	NCT01130688	81
BCR-ABL1 stability	Retaspimycin, tanespimycin	HSP90 inhibitors	NCT00066326, NCT00100997	87
	Arsenic trioxide	PML degradation	NCT00250042, NCT01397734	89
Autophagy pathway	Chloroquine	Autophagy inhibitor	NCT01227135	93,95
Epigenetic regulators	Panobinostat	Pan-HDAC inhibitor	NCT00451035, NCT00686218	100
	Resveratrol, SRT501	SIRT1 inhibitors		102
BCL2 family	Sabutoclax	Pan-BCL2 inhibitor		104
	Omacetaxine	Protein synthesis inhibitor	NCT00375219	108–110
Immunological approaches
IFN-α*	IFN-α	Immunomodulatory agent	NCT00219739, NCT01657604, NCT01392170, NCT00573378	111,112,115
Vaccination	BCR-ABL1 peptides	Vaccine	NCT00267085, NCT00466726	117–119
	WT1	Vaccine	NCT00923910	122
	PR1	Vaccine	NCT00499772, NCT00004918	124,125
	GVAX	Vaccine		126
Cell surface antigens	IL-1RAP mAb CSL362, SL-401 (DT-IL3)	Monoclonal antibody CD123/IL-3R antagonists		127,128
Leukemic stem cell niche
Myeloid cytokines	G-CSF	Cell cycle stimulation		132
Stromal cytokines*: G/GM-CSF; IL-6 placental GF	JAK2 inhibitor, VEGFR1 inhibitor	Inhibition of cytokine signaling; inhibition of PlGF signaling		135,134
Stroma adhesion: CXCL12 pathway N-cadherin/β-catenin	Plerixafor	CXCR4 inhibitor		136,137
Osteoblastic LSC niche	PTH	PTH-TGFβsignaling		139

^*In the authors’ opinion, these are potentially the most promising near-term clinical approaches to be prioritized.