Molecular targets for the treatment of pancreatic cancer: Clinical and experimental studies

Table 1 Current clinical trials for pancreatic cancer

Target molecule	ClinicalTrials.gov identifier	Sponsor	Agent	Treatmentsetting	Studyphase	Comments
EGFR	NCT00561990	Oncoscience AG	Nimotuzumab	First line	II/III	GEM ± nimotuzumab
	NCT02395016	Biotech Pharmaceutical	Nimotuzumab	First line	III	GEM ± nimotuzumab
MEK	NCT01222689	National Cancer Institute	selumetinib	First line	II	Selumetinib + erlotinib
PI3K	NCT01571024	UNC Lineberger Comprehensive Cancer Center	BKM120	First line	I	BKM120 + mFOLFOX6
Akt	NCT01028495	Rexahn Pharmaceuticals	RX-0201	First line	II	RX0201 + GEM
mTOR	NCT00981162	Roswell Park Cancer Institute	Everolimus	Second line	I/II	Everolimus + sorefenib
Angiogenesis	NCT01509911	Tiltan Pharma Ltd	TL-118	First line	II	TL-118 + GEM
Src	FOLFOX-D, NCT01652976	University of Florida	Dasatinib	First line	II	5-Fluorouracil + leucovorin + oxaliplatin + dasatinib
Jak	NCT01423604	Incyte Corporation	Ruxolitinib	Second line	II	Ruxolitinib + capecitabine
	NCT01822756	Incyte Corporation	Ruxolitinib	First line	I	Ruxolitinib + gemcitabine or nab-paclitaxel
Notch	NCT01098344	Cancer Research UK	MK0752	First line	I	MK0752 + GEM
Hedgehog	NCT01130142	Infinity Pharmaceuticals, Inc.	IPI-926	First line	I/II	IPI-926 + GEM
Wnt	NCT01351103	Novartis Pharmaceutical	LGK974	First line	I	LGK974 alone
	NCT01302405	Prism Pharma Co., Ltd.	PRI-724	First line	I	PRI-724 alone
	NCT02050178	OncoMed Pharmaceuticals, Inc	OMP-54 F28	First line	I	GEM + nab-paclitaxel + OMP-54 F28
	NCT02005315	OncoMed Pharmaceuticals, Inc	Vantictumab(OMP-18R5)	First line	I	GEM + nab-paclitaxel + vantictumab
Stroma	Halo-109-202, NCT01839487	Halozyme Therapeutics	PEGPH20(hyaluronidase)	First line	II	GEM + nab-paclitaxel ± PEGPH20
	S1313, NCT01959139	Southwest Oncology Group	PEGPH20	First line	I/II	FOLFIRINOX ± PEGPH20
PARP	NCT01585805	National Cancer Institute	Veriparib	First line	II	GEM + cisplatin ± veriparib
	NCT01296763	Sidney Kimmel Comprehensive Cancer Center	Olaparib	First line	I/II	Irinotecan + cisplatin + mitomycin C ± olaparib
Others	NCT01210911	Academisch Medisch Centrum	Metformin	First line	II	Erlotinib + metformin + GEM
	NCT01373164	Eli Lilly and Company	LY2157299(TGF-b inhibitor)	First line	II	LY2157299 + GEM
	NCT01621243	Momenta Pharmaceuticals, Inc	M402 (heparan sulfate)	First line	I/II	GEM + nab-paclitaxel ±M402
	NCT01783171	National Cancer Institute (NCI)	Dinaciclib	First line	I	Dinaciclib + MK-226

GEM: Gemcitabine.

Table 2 Recent experimental studies of targeted therapy for pancreatic cancer

Targeted therapeutics	Ref.	Cell lines (cell type)	Main results
Multikinase inhibitors
Foretinib	Chen et al[32]	Panc-1(P)	Foretinib inhibited tumor growth, angiogenesis and lymphangiogenesis in xenograft animals, by inhibiting c-MET but VEGFR-2, VEGFR-3, and TIE-2 signaling
SKLB261	Pan et al[80]	BxPC-3 (P),	Application of SKLB261 resulted in more potent antitumor activities than dasatinib, gemcitabine, or erlotinib in pancreatic cancer xenografts
		Panc-1 (P),
		AsPC-1 (S), HPAC (P)
Nintedanib	Awasthi et al[81]	AsPC-1 (S),	A triple angiokinase inhibitor, nintedanib inhibited growth of pancreatic cancer cell lines, with gemcitabine enhancing inhibitory effects
		BxPC-3 (P),
		Panc-1 (P),
		MIA-PaCa-2 (P),
Dual inhibition
Lapatinib and trametinib	Lindberg et al[101]	MAD 08-608, 08-738, 09-366 (P)	Dual anti-EGFR and anti-HER2 therapy significantly enhanced the growth inhibitory effects of the MEK1/2 inhibitor trametinib
ZSTK474 and RO5126766	Van Dort et al[99]	Panc-1 (P)	PI3K inhibitor and the Raf/MEK inhibitor RO5126766 resulted in high in vitro inhibition of both PI3Kand MEK1 also decreased cellular viability in pancreatic cancer cell line
NVP-AEW541 and lapatinib	Urtasun et al[42]	NP-9, -18, -29 (P)	Combined treatment with the IGF-IR and EGFR/Her-2 inhibitors synergistically inhibited pancreatic cancer cell growth which is associated with abolishment of Akt, Efk, and IRS-1 activity
		CP15T, ,15A (p)
Novel pathways
PX-478 (HIF-a)	Zhao et al[84]	CFPAC-1 (S), BxPC-3 (P),	Combined treatment with gemcitabine/PX-478 significantly enhanced the anti-tumor effect which is associated with immunogenic cell death
		Panc-1 (P),
		MIA-PaCa-2 (P)
SB216763(GSK-3b)	Marchand et al[86]	Panc-1 (P),	Inhibition of GSK-3βn induced apoptosis by mechanism involving JNK-cJUN activation
		MIA-PaCa-2 (P), BxPC-3 (P)
Micro RNA
miR-142-3p	MacKenzie et al[95]	MIA-PaCa-2 (P), Capan-1(S),	A unique HSP70 inhibiting compounds, miR-142-3p regulate triptolide-induced inhibition of pancreatic cancer growth
		HEK-293 (P),
		S2-013 (P)
miR-146a	Li et al[96]	AsPC-1 (s),	miR-146a takes significant roles in pancreatic cancer invasion and metastasis but lower expressed in pancreatic cancer compared with normal pancreatic tissue
		Panc-1 (P)
miR-494	Li et al[97]	Colo357 (s),	miR-494, identified to affect levels of FOXM1 in pancreatic cancer cell lines and act as a negative regulator of this transcriptional activator, blocked nuclear translocation β-catenin
		Panc-1 (P)

VEGF: Vascular endothelial growth factor; EGFR: Epidermal growth factor receptor; HER2: Human epidermal growth factor receptor 2; MEK: Mitogen-activated ERK kinase; PI3K: Phosphatidylinositol-3 kinase; IGF-1R: Insulin-like growth factor 1 receptor; FGFR: Fibroblast growth factor receptor; HSP: Heat shock protein; FOXM1: Forkhead box M1; P: Primary; S: Secondary.