STATs are transcription factors which are normally present in the cytoplasm and activated by inflammatory signalling associated with epithelial to mesenchymal transition (EMT) which leads to their nuclear import . STAT3 expression is maintained and constitutive activation has been reported in at least 30% of pancreatic cancers .
Fatty acid synthase (FASN) is a key enzyme involved in lipogenesis and the production of long-chain fatty acids from acetyl-coenzyme A (CoA) and malonyl-CoA which is crucial for rapidly growing cancer cells including pancreatic . The inhibition of fatty acid synthase is known to increase reactive oxygen species (ROS) levels in cancer which is associated with apoptosis .
Focal Adhesion Kinase (FAK) inhibitors demonstrated in preclinical pancreatic cancer models increased mouse survival time via tumour stasis, reduced collagen deposition and reduced numbers of activated fibroblasts, down-regulated gene expression of fibrosis associated markers, reduced cancer stem-like cell numbers, reduced numbers of immunosuppresive cells within tumours, synergized with gemcitabine treatment, synergized with adoptive T cell transfer to reduce tumour volume and was associated with increased numbers of therapeutic T cell in the tumour and synergised with checkpoint inhibitors under certain circumstances .
|Figure 1: HO-3867 mechanisms of action in cancer cells. HO-3867 down-regulates FASN and FAK protein expression leading to apoptosis and decreased cell migration respectively. HO-3867 also inhibits STAT3 phosphorylation which leads to apoptosis and possibly decreased cell migration.|
The curcumin analog HO-3867 has recently been shown to inhibit STAT3 and down-regulate fatty acid synthase in pancreatic cancer cells leading to apoptosis via ROS . In addition in ovarian cancer models HO-3867 down-regulates FAK . The potential to inhibit STAT3, FASN and FAK with a single agent is very promising and warrants further investigation as a potential therapeutic for pancreatic cancer (Figure 1).
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