Table 1.

Summary of therapeutic agents that target the leukaemic niche in the bone marrow microenvironment.

Target Pathways	Target Strategy	Agents	Mechanism of Action in the BMM	Leukaemia Type Investigated	Animal Studies	Clinical Studies
CXCL12/ CXCR4 signalling pathway	CXCR4 Inhibitor (bicyclams)	Plerixafor (AMD3100)	Induces mobilisation and chemosensitivity of leukaemic cells by targeting CXCL12/CXCR4 interactions.	AML, pre-B ALL	[43,44,45]	[46,47,48] FDA-A
		AMD3465	Induces mobilisation and chemosensitivity of leukaemic cells by targeting CXCL12/CXCR4 interactions.	AML, Pre-B ALL, T-ALL	[45,49,50]	N/R
		AMD11070	Induces mobilisation and chemosensitivity of leukaemic cells by targeting CXCL12/CXCR4 interactions.	Pre-B ALL	[51]	N/R
	CXCR4 inhibitor (synthetic peptides)	BL-8040 (BKT140)	Induces mobilisation and chemosensitivity of leukaemic cells by targeting CXCL12/CXCR4 interactions. Induces apoptosis in leukaemic cells.	AML	[52]	[53]
		LY2510924	Induces mobilisation and chemosensitivity of leukaemic cells by targeting CXCL12/CXCR4 interactions. Inhibits proliferation of leukaemic cells.	AML	[54]	[55]
		E5 Peptide	Induces mobilisation and chemosensitivity of leukaemic cells by targeting CXCL12/CXCR4 interactions. Induces apoptosis in leukaemic cells.	AML	[56,57]	N/R
		POL6326	Induces mobilisation and chemosensitivity of leukaemic cells by targeting CXCL12/CXCR4 interactions.	AML	[58]	NCT01413568Phase I/II #
	Anti-CXCR4 monoclonal antibody	Ulocuplumab	Induces apoptosis and blocks CXCL12-induced leukaemic cell migration. Induces mobilisation of leukaemic cells.	AML	[59]	[60,61]
		LY2624587	Induces apoptosis and blocks CXCL12-induced leukaemic cell migration.	T-ALL	[62]	N/R
	CXCL12 inhibitor	CX-01	Inhibits binding of CXCL12 to immobilised heparin and enhances treatment efficacy.	AML	N/R	[63]
Notch signalling pathway	Gamma-secretase inhibitor	PF-03084014	Inhibits stromal-mediated chemoresistance and potentiates sensitivity of leukaemic cells to chemotherapy. Inhibits proliferation and induces apoptosis in leukaemic cells.	T-ALL	[64,65]	[66]
		BMS-906024	Inhibits growth and survival of leukaemic cells by targeting Notch signalling.	T-ALL	[67]	[68]
		MRK-560	Promote leukaemic cell cycle arrest by targeting PSEN1, a subclass of gamma-secretase complexes highly involved in activation of mutant Notch1.	T-ALL	[69]	N/R
Wnt/β-catenin signalling pathway	Wnt/β-catenin inhibitor	XAV939	Attenuates BMM-induced protection of leukaemic cells by inhibiting Wnt signalling. Inhibits proliferation of leukaemic cells.	Pre-B ALL	[70]	N/R
		PRI-724	Attenuates BMM-induced protection of leukaemic cells by inhibiting Wnt signalling. Induces apoptosis in leukaemic cells.	AML, CML	[71,72]	NCT01606579Phase I/II #
		BC2059	Induces apoptosis of leukaemic cells by synergistically enhancing the effect of drug treatment.	AML	[73]	N/R
		CWP232291	Promotes endoplasmic reticulum stress activation, leading to degradation of β-catenin and apoptosis induction in leukaemic cells.	AML	N/R	[74]
	Wnt/β-catenin/FLT3 inhibitor	SKLB-677	Induces apoptosis in leukaemic cells.	AML	[75]	N/R
Adhesion molecules signalling pathway	Anti-CD44 monoclonal antibody	RG7356/ ARH460-16-2	Blocks leukaemia–stroma interaction by targeting CD44.	AML	[76]	[77]
	Anti-α4β1/ VLA-4 monoclonal antibody	Natalizumab	Blocks leukaemia–stroma interaction by targeting VLA-4/VCAM-1, sensitising leukaemic cells to chemotherapy.	AML, Pre-B ALL	[78,79]	N/R FDA-A
	α4 inhibitor	TBC3486	Blocks leukaemia–stroma interaction by targeting integrin α4, sensitising leukaemic cells to chemotherapy.	Pre-B ALL	[80]	N/R
	VLA-4 peptide antagonist	FNIII14	Blocks cell adhesion by targeting VLA-4 to fibronectin interaction, sensitising leukaemic cells to chemotherapy.	AML	[81]	N/R
	E-selectin inhibitor	Uproleselan (GMI-1271)	Attenuates cell surface adhesion, regeneration and survival of leukaemic cells by antagonising E-selectin. Sensitises leukaemic cells to chemotherapy.	AML	[34]	[82] NCT03701308 NCT03616470 Phase II/III #
	Dual CXCR4/ E-selectin inhibitor	GMI-1359	Promotes leukaemic cell mobilisation and restores normal haematopoiesis.	AML	[83]	N/R
Bone remodelling signalling pathway	Bone resorption inhibitor	Zoledronic acid	Inhibits osteoclast resorption.	Pre-B ALL	[35]	N/R FDA-A
	mTOR inhibitor	Everolimus	Inhibits osteoclast resorption. *	ALL	N/R	[84,85] FDA-A
	Receptor tyrosine kinase inhibitor	Cabozantinib	Inhibits osteoclast differentiation and resorption, modulates RANKL/osteoprotegerin in osteoblasts. * Induces apoptosis in leukaemic cells.	AML	[86]	[87] FDA-A
	Proteasome inhibitor	Bortezomib	Promotes osteoblast differentiation and suppress osteoclast activity. * Induces apoptosis in leukaemic cells.	AML, Pre-B ALL, T-ALL	[88,89]	[90,91] FDA-A
		Carfilzomib	Promotes osteoblast differentiation and suppress osteoclast activity. * Induces apoptosis in leukaemic cells.	AML, ALL	[92,93]	[94,95] NCT02303821 NCT02512926 Phase I FDA-A
		Ixazomib	Promotes osteoblast differentiation and suppress osteoclast activity. *	AML	N/R	[96] FDA-A
Hypoxia-related signalling pathway	Hypoxia activated prodrug	PR-104	Induces cytotoxicity in hypoxic leukaemic cells.	AML, Pre-B ALL, T-ALL	[97,98]	[99]
		Evofosfamide (TH-302)	Induces cytotoxicity in hypoxic leukaemic cells.	AML, ALL	[100,101]	[102]
Vasculature-associated pathway	Vascular disrupting agent	CA1P (OXi4503)	Induces breakdown of vascular architecture.	AML	[103]	[104]

N/R indicates not reported and status remains unclear. # ongoing clinical studies as described in the relevant reference or clinical trial number. * therapeutic mechanisms on bone remodelling confirmed using non-leukaemic animal models but remain to be confirmed in leukaemia animal models. FDA-A refers to agents clinically approved by the FDA for other disease treatments. ALL, acute lymphoblastic leukaemia; AML, acute myeloid leukaemia; BMM, bone marrow microenvironment.