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.