Pilot study of the antifibrotic effects of the multikinase inhibitor pacritinib in a mouse model of liver fibrosis

Abstract

BackgroundFibrotic diseases result from an exuberant response to chronic inflammation. Myelofibrosis is the end result of inflammation in bone, caused by an inflammatory process triggered by production of abnormal myeloid cells driven by mutations affecting the JAK–STAT pathway. Inflammatory cytokine overproduction leads to increased mesenchymal cell proliferation, culminating in fibrosis. Although JAK2 inhibitors, such as the JAK1/2 inhibitor ruxolitinib and the JAK2/FLT3/CSF1R/IRAK1 inhibitor pacritinib suppress abnormal clone expansion in myelofibrosis, ruxolitinib does not appear to prevent or reverse bone-marrow fibrosis in most patients. In two Phase III clinical trials, pacritinib, however, demonstrated improvements in platelet counts and hemoglobin and reductions in transfusion burden in some patients with baseline cytopenias, suggesting it may improve bone-marrow function. Unlike ruxolitinib, pacritinib suppresses signaling through IRAK1, a key control point for inflammatory and fibrotic signaling.PurposeTo investigate potential antifibrotic effects of pacritinib in an animal model of liver fibrosis relevant to the observed course of human disease.MethodsPacritinib, negative control (vehicle), and positive control (the angiotensin 2-receptor antagonist and PPARγ partial agonist telmisartan) were assessed in the murine Stelic animal model, which mimics the clinically observed progression from hepatic steatosis to nonalcoholic steatohepatitis, liver fibrosis, and hepatocellular carcinoma. Histopathological analysis used hematoxylin and eosin staining. Body and liver weight changes, nonalcoholic fatty-liver disease activity scores, and plasma cytokeratin 18 fragment levels (a biomarker of hepatic necrosis) were measured.ResultsPacritinib-treated mice had significantly (P<0.01) reduced fibrotic areas in liver compared to vehicle control and significantly (P<0.05) lower levels of CK18. The antifibrotic effect of pacritinib was comparable to that of telmisartan, but without significant effects on fat accumulation.ConclusionThese results, the first to demonstrate hepatic antifibrotic effects for pacritinib in an animal model of liver disease, provide preliminary support for potential clinical applications of pacritinib in fibrotic diseases other than myelofibrosis.

JAK/STAT signaling in hepatocellular carcinoma

“…Thus, this study demonstrates the potential of pacritinib, as the JAK inhibitor could prolong survival periods in clinically relevant models. In HCC, pacritinib was found to reduce liver fibrosis in mouse models that mimic clinical HCC development and progression from hepatic steatosis [88]. High levels of CK-18, which predicts for increased fibrosis, was also effectively reduced in these mice upon treatment with pacritinib [88].…”

“…In HCC, pacritinib was found to reduce liver fibrosis in mouse models that mimic clinical HCC development and progression from hepatic steatosis [88]. High levels of CK-18, which predicts for increased fibrosis, was also effectively reduced in these mice upon treatment with pacritinib [88]. Given that liver fibrosis occurs in most patients with HCC, the antifibrotic effects of pacritinib observed in relevant disease models offer promising clinical applications for HCC treatment.…”

Inhibition of interleukin-1 receptor-associated kinase 1 (IRAK1) as a therapeutic strategy

“…In a mouse model of liver fibrosis that recapitulates the stepwise, clinically observed progression from nonalcoholic fatty liver disease (NAFLD, an increasingly common, known risk factor for liver-related mortality [ 92 ]) to nonalcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), pacritinib, presumably through IRAK1 signaling inhibition, significantly reduced liver fibrotic area compared with vehicle control without affecting steatosis [ 93 ]. Plasma CK-18 fragment levels, a clinical biomarker of liver cell necrosis, were also significantly reduced.…”

“…Thus, macrophage STK4 may be protective in inflammation-induced HCC via IRAK1, and its deficiency mitigated by IRAK1 inhibition. In a murine hepatic steatosis and fibrosis model that leads to a high proportion of HCC, pacritinib was found to prevent fibrosis and to decrease serum levels of a marker for hepatocyte necrosis, cytokeratin 18, suggesting that suppression of IRAK1 may be beneficial in preventing premalignant fibrosis [ 93 ].…”

“…JAK inhibitors, such as ruxolitinib [ 181 , 182 ] and pacritinib [ 32 , 33 , 183 ], have demonstrated clinical efficacy in MPNs. As previously described, pacritinib, but not ruxolitinib, also inhibits IRAK1 at clinically attainable levels, which may impart additional benefits [ 93 ]. Further studies, however, are needed to confirm such effects and determine whether its IRAK1 inhibition plays a role in its clinical profile.…”