New targeted therapies in pancreatic cancer

Table 1 Results of different studies concerning new targeted therapy

Ref.	Patients no./disease stage	Study type	Drugs	OS	PFS	Benefit
Burtness et al[19], 2014	87/metastatic	II RCT	Docetaxel + Irinotecan ± Cetuximab	6.5 vs 5.4	3.9 vs 4.5	Negative
Fensterer et al[20], 2014	73/resected	II	GEM + Cetuximab	22.4	NA	Negative
Philip et al[21], 2010	743/locally advanced or metastatic	III RCT	GEM ± Cetuximab	5.9 vs 6.3	3 vs 3.5	Negative
Munter et al[22], 2008	66/locally advanced	II RCT	RT + GEM ± Cetuximab	15	-	Negative
Lim et al[23], 2014	127/locally advanced	Retrospective	GEM + Capecitabine vs GEM + Erlotinib vs GEM	21 vs 12 vs 15	8.9 vs 5.2 vs 3.9	Negative for Erlotinib
Philip et al[24], 2014	10/metastatic	I RCT	GEM + Erlotinib + Cixutumumab vs GEM + Erlotinib	7 vs 6.7	3.6 vs 3.6	Negative
Watkins et al[25], 2014	44/advanced	II	GEM + Capecitabine + Erlotinib +Bevacizumab	12.6	8.4
Herman et al[26], 2013	48/metastatic	II	Capecitabine + Erlotinib + RT followed by GEM + Erlotinib	24.4	15.6
Feliu et al[27], 2011	42/advanced	II RCT	GEM + Erlotinib	8	5	Negative
Moore et al[28], 2007	569/advanced	III RCT	Gem + Erlotinib vs GEM	6.2 vs 5.9	3.7 vs 3.5	Positive
Harder et al[29], 2012	17/metastatic HER2+	II	Capecitabine + Trastuzumab	6.9	12.5	Negative
Safran et al[30], 2004	34/metastatic	II	Gemcitabine + Trastuzumab	7		Negative
Bodoky et al[31], 2012	70/advanced	II	Capecitabine vs Selumetinib	5 vs 5.4	88% vs 84%	Negative
Infante et al[32], 2014	160/metastatic	II RCT	GEM + Trametinib vs GEM	8.4 vs 6.7	-	Negative
Fuchs et al[33], 2015	322/metastatic	III RCT	GEM + Ganitumab vs GEM	7.2 vs 7	3.7 vs 3.6	Negative
McCaffery et al[34], 2013	84/metastatic	IIRCT	GEM+Ganitumab vs GEM	16 vs 5.9		Positive
Kindler et al[35], 2012	125/metastatic	II RCT	GEM + Ganitumab vs GEM + Conatumumab vs GEM	8.7 vs 7.5 vs 5.9	5.1 vs 4 vs 2	Positive
Bramhall et al[36], 2002	239/advanced	RCT	GEM + Marimastat vs GEM	165.5 d	92.5 d	Negative
De Jesus-Acosta et al[37], 2014	17/metastatic second line therapy	I	GEM+ inhibitor γ secretase	4	1.5	Positive
Goldstein et al[38], 2015	861/metastatic	III RCT	GEM + Nab-paclitaxel vs GEM	8.7 vs 6.6	-	Positive
Hosein et al[39], 2013	19/advanced second line therapy	II	GEM + Nab-paclitaxel	7.3	-	Positive
Pant et al[40], 2014	30/advanced locally	II	GEM + Capecitabine Bevacizumab	10.4		Negative
Kindler et al[41], 2010	535/advanced	III RCT	GEM + Bevacizumab vs GEM	5.8 vs 5.9	3.8 vs 2.9	Negative
Crane et al[42], 2009	82/advanced	II	RT + capecitabine+bevacizumab, followed by GEM + bevacizumab	11.9		Negative
Ko et al[43], 2010	36/metastatic GEM refractory	II	Bevacizumab + Erlotinib	102 d		Negative
Van Cutsem et al[44], 2009	607/metastatic	III RCT	GEM + erlotinib + bevacizumab vs GEM + erlotinib	7.1 vs 6	4.6 vs 3.6	Negative
IokaT et al[45], 2015	632/advanced	III RCT	GEM + axitinib vs GEM	5.1 vs 5.4	-	Negative
Spano et al[46], 2008	103/advanced and metastatic	II RCT	GEM + axitinib vs GEM	6.9 vs 5.6	-	Negative
Kindler et al[47], 2011	632/advanced or metastatic	III RCT	GEM + axitinib vs GEM	8.5 vs 8.3	-	Negative
Rougier et al[48], 2013	427/metastatic	III RCT	GEM + Aflibercept vs GEM	6.5 vs 7.8	3.7 vs 3.7	Negative
Chiorean et al[49], 2014	27/advanced		GEM + Sorafenib followed by RT + GEM	12.6	10.6	Negative
Cascinu et al[50], 2014	144/advanced	II RCT	GEM + Cisplatin + Sorafenib vs GEM + Cisplatin	7.5 vs 8.3	4.3 vs 4.5	Negative
Gonçalves et al[51], 2012	104/advanced or metastatic	IIIRCT	GEM + Sorafenib vs GEM	5.7 vs 3.8	9.2 vs 8	Negative

OS: Overall survival; PFS: Progression free survival; RCT: Randomized control trial; Advanced diseases: Locally advanced and metastatic; RT: Radiotherapy; GEM: Gemcitabine.

Table 2 Potential therapeutic targets using miRNA

Ref.	miRNA	Oncogene/tumor suppressor	Target genes	Cellular process affected
Moriyama et al[99], 2009	miR-21	Oncogene	CDK6, PDCD4, CDKN1A, FAS, IL6R, SOCS5, APAF1, NFlB, TPM1	Apoptosis, cell proliferation, cell invasion
Park et al[94], 2009	miR-221	Oncogene	CDKN1B, CDKN1C, KIT	Cell migration, proliferation
Habbe et al[100], 2009	miR-155	Oncogene	AGTR1, APC, ARID2, BACH1, CEBPB, CYR61, DET1, EDN1, ETS1, FADD, FGF7, FOXO3	Cell migration
Chen et al[101], 2011	miR-196a	Oncogene	NRAS, HOXB8, HMGA2, ANXA1	Cell growth and differentiation
Cai et al[95], 2013	miR-181b	Oncogene	BCL2	Sensitization to gemcitabine
Yan et al[96], 2010	miR-20a	Oncogene	STAT3, CDH1	Proliferation and invasion
Torrisani et al[102], 2009	Let-7	Tumor suppressor	KRAS, HMGA2, TRIM71, NF2	Cell proliferation
Ji et al[98], 2009	miR-34a	Tumor suppressor	NOTCH1, BCL2, E2F3, VEGFA, SIRT1, CCND1, CDK6	Apoptosis, cell proliferation
Zhao et al[103], 2010	miR-217	Tumor suppressor	KRAS, SIRT1, PTEN	Cell proliferation, invasion
Yu et al[97], 2010	miR-96	Tumor suppressor	KRAS	Invasion, cell migration, apoptosis
Li et al[104], 2010	miR-146a	Tumor suppressor	EGFR	Invasion
Hou et al[105], 2012	miR-216a	Tumor suppressor	PTEN, CDC42, CD44, SIRT1	Tumorigenicity

Table 3 Studies with monoclonal antibodies that target the tumor stromal component

Ref.	Stromal component	Therapeutic target	Treatment
Strimpakos et al[106], 2013	Extracellular matrix	Hyaluronan	PEGPH20
Bramhall et al[36], 2002	Extracellular matrix	Metalloproteinase	Marimastat
Stephenson et al[107], 2011	Signaling pathways	Hedgehog	Vismodegib (GDC-0449)
Oettle et al[108], 2009	Signaling pathways	Transforming growth factor β receptor	Trabedersen
Yabuuchi et al[109], 2013	Signaling pathways	Notch	PF-03084014
Brahmer et al[106], 2012	Immune cells	Receiver for programmed cell death	BMS-936559
Le et al[111], 2013	Immune cells	Cytotoxic T-lymphocyte antigen 4	Ipilimumab
Beatty et al[112], 2013	Immune cells	CD40	CP-870893
Lutz et al[113], 2011	Immune cells	CB8	GVAX
Laheru et al[114], 2008	Immune cells	CB8	GVAX

GVAX: Granulocyte-macrophage colony-stimulating factor vaccine.