Targeting inflammation in pancreatic cancer: Clinical translation

Table 1 Preclinical assessment of inflammatory targets in pancreatic adenocarcinoma

Target	Drug	PMID	Year	Authors summaries
Hedgehog acyltransferase (Hhat)	RU-SKI 43	24469057	2015	In vivo mouse study targeting Hedgehog acyltransferase (Hhat). A lentivirally delivered hairpin RNA impeded the proliferation of pancreatic cancer in vitro and in vivo
Hedgehog	GDC-0449	25679326	2015	Combination therapy with GDC-0449 or miR-let7b vs single agent therapy effectively inhibited tumor growth when injected to athymic nude mice bearing ectopic tumors generated using MIA PaCa-2 cells
Sonic hedgehog pathways	Ormeloxifene	25840985	2015	Ormeloxifene caused potent inhibition of the SHH signaling pathway via downregulation of SHH and its related important downstream targets. Ormeloxifene potentiated the antitumorigenic effect of gemcitabine by 75% in PDAC xenograft mice
Hedgehog pathway	MEDI-5304	24344235	2014	MEDI-5304 displayed robust pharmacodynamic effects in stromal cells that translated to antitumor efficacy as a single agent in an HT-29/MEF coimplantation model of paracrine hedgehog signaling. MEDI-5304 also improved responses to carboplatin in the HT-29/MEF model. The antibody, however, had no effect as a single agent or in combination with gemcitabine on the CSC frequency or growth of several primary pancreatic cancer explant models
Hedgehog	GDC-0449	25278454	2014	GDC-0449 for 3 wk leads to downmodulation of GLI1 and PTCH1, without significant changes in CSCs compared with baseline. GDC-0449 and gemcitabine were not superior to gemcitabine alone in the treatment of metastatic pancreatic cancer
Hedgehog pathway	Metformin	24692708	2014	In vitro, BxPC3 human pancreatic cancer cells were treated with metformin, and Sonic hedgehog (Shh) mRNA and protein levels were examined. Metformin reduces the expression of Shh in several cancer cell lines including pancreatic cancer cells
Hedgehog	Curcumin	23563640	2013	Curcumin can inhibit the proliferation of TGF-β1-stimulated PANC-1 cells, it can induce apoptosis, and reverse the EMT. The possible underlying molecular mechanisms are through inhibition of the Shh-GLI1 signaling pathway
COX 5-lipoxygenase (5-LOX)	Dietary licofelone	25906749	2015	In vivo mouse study of licofelone, an agent that targets both COX-2 and 5-LOX
LOX	Zileuton	25483364	2014	Zileuton suppressed the proliferation of SW1990 cells in a concentration- and time-dependent manner. In addition, zileuton induced SW1990 cells to undergo apoptosis and significantly decreased 5-LOX expression
STAT3	Thiosemicarbazones	25561562	2015	In vitro and in vivo iron-binding ligands inhibit constitutive and interleukin 6-induced activation of STAT3 signaling DFO, Dp44mT, and DpC significantly decreased constitutive phosphorylation of the STAT3 transcription factor at Tyr705 in the pancreatic cancer cell lines and when injected in vivo
STAT3	Aspirin metformin	26056043	2015	Metformin combined with aspirin significantly inhibited the phosphorylation of mTOR and STAT3, and induced apoptosis as measured by caspase-3 and PARP cleavage Taken together, the combination of metformin ad aspirin significantly inhibited pancreatic cancer cell growth in vitro and in vivo
JAK2 STAT3	MicroRNA (miR)-216a	25220761	2014	MiR-216a overexpression markedly inhibited the JAK2/STAT3 signaling pathway and xenograft tumor growth in vivo
ALK pathway including STAT3	Crizotinib	25193856	2014	Crizotinib strongly suppressed the growth and proliferation of pancreatic cancer cells in a dose-dependent manner. Crizotinib strongly inhibited the expression of activated ALK in pancreatic cancer cells, modulating its downstream mediators such as STAT3, AKT, and ERK
STAT3 NF-κB COX-2 EP4	Nexrutine	24520096	2014	Nexrutine treatment inhibited growth of pancreatic cancer cells through induction of apoptosis Reduced levels and activity of STAT3, NF-κB, and their crosstalk led to transcriptional suppression of COX-2 and subsequent decreased levels of prostaglandin E2 (PGE2) and PGF2. Nexrutine intervention reduced the levels of NF-κB, STAT3, and fibrosis in vivo. Expression of prostaglandin receptor EP4 that is known to play a role in fibrosis was significantly elevated in human pancreatic tumors. Dual inhibition of STAT3-NF-κB by Nexrutine may overcome problems associated with inhibition of either pathway
JAK/STAT Src/FAK	Guggulsterone	23920124	2013	In vitro, guggulsterone treatment decreased mucin MUC4 expression in Capan1 and CD18/HPAF cells through transcriptional regulation by inhibiting Jak/STAT pathway
Notch JAK2	GSI IX and AG-490	24293409	2014	Combinational treatment with anti-NOTCH and JAK/STAT drugs significantly attenuates tumor progression in vivo and suppresses conversion from acinar-ductal-metaplasia to PDAC

Outlines the significant interest shown by preclinical researchers in targeting inflammation in PDAC. Using the search criteria pancreatic cancer/pancreatic adenocarcinoma + hedgehog, JAK/STAT, LOX we identified preclinical studies that have attempted to assess therapeutics targeted against these important inflammatory mediators of PDAC progression in the past 2 years. We have included those published in journals with an impact factor > 5. PDAC: Pancreatic adenocarcinoma; PARP: Poly-ADP-ribose polymerase; JAK: Janus kinase; STAT: Signal transducer and activator of transcription.