Table 1.

The pre-clinical and clinical studies targeting PCa cells associated with signaling pathways in the bone microenvironment.

Pathway	Drug/agent	Target PCa	Drug development stage	Description	Citation
Notch	PF-03084014	mCRPC, CSC	Pre-clinical	γ-secretase inhibitor	Cui et al., 2015
	GSI	mCRPC, CSC	Pre-clinical	γ-secretase inhibitor	Stoyanova et al., 2016
	DBZ	Metastatic	Pre-clinical	Notch inhibitor	Qui et al., 2018
	RO4929097	mCRPC	Clinical (phase II) NCT01200810	γ-secretase/Notch inhibitor	NCI, 2010–2017
Wnt	LGK974	Metastatic	Pre-clinical	Wnt inhibitor blocks porcupine-a membrane-bound O-acyltransferase	Ma et al., 2016
	ICG00I	Metastatic, CSC	Pre-clinical	β-catenin inhibitor	Zhang et al., 2018
	Ipafricept (OMP-54F28)	Advanced, CSC	Clinical (Phase I) NCT01608867	frizzled 8 receptor fused IgG1 Fc	Jimeno el al., 2017
	Foxy-5	Metastatic	Clinical (Phase I) NCT02020291 NCT02655952	Formylated 6 amino acid peptide targets Wnt-5a	WntResearch AB, 2013–2016; WntResearch AB, 2016–2017
Hedghog	GANT61	Metastatic	Pre-clinical	Gli inhibitor	Lauth et al., 2007; Rimkus et al, 2016
	Sonidegib (erismodegib, LDE225)	Metastatic, CSC	Pre-clinical	Hh inhibitor	Nanta et al., 2013
	Sonidegib	Advanced	Clinical (Phase I) NCT021111870	Hh inhibitor	Ross et al., 2017
	Vismodegib	mCRPC	Clinical NCT02115828	Hh inhibitor	Maughan et al., 2016
	Itraconozale	Advanced	Clinical (Phase II) NCT018787331	Antifungal agent	Lee et al., 2019
FGF	AZ8010	Metastatic	Pre-clinical	FGFR inhibitor	Feng et al., 2012
	PD173074/CH5183284	Metastatic	Pre-clinical	FGFR antagonist targeting FGFRI	Bluemn et al., 2017
	Dovitinib (TK12S8)	Metastatic and osteoblasts	Pre-clinical	FGFR inhibitor	Wan et al., 2014;Yadav et al., 2017
	Dovitinib	mCRPC	Clinical (Phase II) NCT01741116	FGFR inhibitor	Choi et al., 2018
	Nintedanib (BIBF1120)	Metastatic	Pre-clinical	FGFR inhibitor	da Silva et al., 2017, 2018
	Nintedanib	mCRPC	Clinical (Phase I, II) NCT02856425 NCT00706628	FGFR inhibitor	Bousquet el al., 2011; Droz el al., 2014; Gustave Roussy, Paris 2016–2018; Boehringer Ingelheim, 2008–2016
TGFβ	Tranilast	Metastatic	Pre-clinical	Anti-allergic agent targets TGFβl	Izumi et al., 2009
	IN-1130	Metastatic	Pre-clinical	TGFβRI ALK-5 kinase inhibitor	Lee et al., 2008
	SB-431542	Metastatic	Pre-clinical	TGFβRI ALK-5 kinase inhibitor	Miles et al., 2012
	LY2109761	Metastatic	Pre-clinical	TGFβRI & RII kinase inhibitor	Wan et al., 2012
	Galunisertib (LY2157299)	Metastatic	Pre-clinical	TGFβRI kinase inhibitor	Paller et al., 2018
	Galunisertib	mCRPC	Clinical (Phase II) NCT02452008	TGFβRI kinase inhibitor	Johns Hopkins, 2016–2021
CXCL12	CTCE-0908 (CTE9908) or Plerixafor (AMD3100)	Metastatic	Pre-clinical	CXCR4 antagonist	Gravina et al., 2015
	Plerixafor	Metastatic. CSC	Pre-clinical	CXCR4 antagonist; DTC mobiliser by blocking the CXCR4	Shiozawa et al., 2011; Dubrovska et al., 2012; Gravina et al., 2015; Wang et al., 2015; Conley-LaComb et al., 2016; Jung et al., 2018
	Plerixafor	Metastatic	Clinical NCT02478125	CXCR4 antagonist; DTC mobiliser by blocking the CXCR4	Johns Hopkins. 2015–2017
GAS6	Bemcentinib (R428, BOB-324)	Metastatic	Pre-clinical	Axl inhibitor blocks autophosphorylation of Axl	Bansal el al., 2015
	Amuvatinib (MP470)	Metastatic	Pre-clinical	Axl inhibitor blocks ATP-binding cassette Bl (ABCB1)	Lin et al., 2017
	UNC1062	Metastatic, CSC	Pre-clinical	Mer inhibitor blocks autophosphorylation of Mer	Shiozawa et al., 2016; Jung et al., 2016
	Cabozantinib (XL-184, Exelixis)	mCRPC	Pre-clinical	Tyrosine kinase inhibitor (c-Met, VEGFRs, Alk, Ron, and Axl)	Graham et al., 2014; Dai et al., 2014; Stern and Alvares, 2014; Haider et al., 2015; Leibowitz-Amit et al., 2016
	Cabozantinib	mCRPC	Clinical (Phase II, III) NCT01605227 NCT01522443	Tyrosine kinase inhibitor (c-Met, VEGFRs, Alk, Ron, and Axl)	Exelixis, 2012–2018; Smith et al., 2013; Smith et al., 2014; Smith et al., 2016
	Foretinib (GSK1363089, XL880)	Advanced	Clinical (Phase II) NCT00726323	Tyrosine kimse inhibitor (c-Met, VEGFRs, Alk, Ron, and Axl)	GlaxoSmithKline, 2008–2017; Choueiri et al., 2013