Antitumor effects of regorafenib and sorafenib in preclinical models of hepatocellular carcinoma

Abstract

The purpose of this study was to investigate the antitumor activity of regorafenib and sorafenib in preclinical models of HCC and to assess their mechanism of action by associated changes in protein expression in a HCC-PDX mouse model. Both drugs were administered orally once daily at 10 mg/kg (regorafenib) or 30 mg/kg (sorafenib), which recapitulate the human exposure at the maximally tolerated dose in mice.In a H129 hepatoma model, survival times differed significantly between regorafenib versus vehicle (p=0.0269; median survival times 36 vs 27 days), but not between sorafenib versus vehicle (p=0.1961; 33 vs 28 days). Effects on tumor growth were assessed in 10 patient-derived HCC xenograft (HCC-PDX) models. Significant tumor growth inhibition was observed in 8/10 models with regorafenib and 7/10 with sorafenib; in four models, superior response was observed with regorafenib versus sorafenib which was deemed not to be due to lower sorafenib exposure. Bead-based multiplex western blot analysis was performed with total protein lysates from drug- and vehicle-treated HCC-PDX xenografts. Protein expression was substantially different in regorafenib- and sorafenib-treated samples compared with vehicle. The pattern of upregulated proteins was similar with both drugs and indicates an activated RAF/MEK/ERK pathway, but more proteins were downregulated with sorafenib versus regorafenib. Overall, both regorafenib and sorafenib were effective in mouse models of HCC, although several cases showed better regorafenib activity which may explain the observed efficacy of regorafenib in sorafenib-refractory patients.

Biomarkers Associated With Response to Regorafenib in Patients With Hepatocellular Carcinoma

“…3,4 The broader approach used in this study is not only biologically warranted considering the heterogeneity of HCC tumors, 15,27 but is also needed due to the multiple targets and pathways affected by MKIs such as regorafenib. 7 Recent protein expression analysis of regorafenib and sorafenib has revealed a complex and distinct pattern of protein expression, which may provide some rationale as to why regorafenib is active in sorafenib-refractory patients. Disease heterogeneity and multikinase inhibition also make it perhaps unlikely that a single target will be identified that can predict treatment benefit.…”

“…5,6 Protein expression analyses in an HCC preclinical model have confirmed a complex expression pattern with regorafenib that is different from that of sorafenib. 7 This complex pattern, along with disease heterogeneity, may make the identification of biomarkers challenging.…”

Genomic analysis of small nucleolar RNAs identifies distinct molecular and prognostic signature in hepatocellular carcinoma

“…However, the prognosis for patients with unresectable advanced-stage HCC remains poor (6,7). Sorafenib was the only systemic drug available for treating advanced HCC until the recent approval of regorafenib, another multi-kinase inhibitor (8,9). However, sorafenib and regorafenib have a low durable response rate and their benefit for survival is limited (10).…”

F127 poloxamer effect on cytotoxicity induction of tumour cell cultures treated with doxorubicin

“…Considering the acidic environment of HCC tissue, the copolymer studied herein might be further slightly modified to generate acid‐cleavable non‐ionic surfactants targeting its delivery to the tumour, and hence, increasing the efficacy and selectivity of the antitumoral treatment, and lowering individual and cumulative anthracycline doses. Likewise, it is tempting to speculate that this general phenomenon might also occur with recently proposed HCC systemic therapeutics (such as regorafenib, approved by FDA in 2017) …”

“…Likewise, it is tempting to speculate that this general phenomenon might also occur with recently proposed HCC systemic therapeutics (such as regorafenib, approved by FDA in 2017). [29] Further experimentsby using either a drug-resistant cell line or even cancer cells from patientsare clearly warranted to perform an accurate RRI calculation. Likewise, future studies about the underlying mechanism involved in such encouraging observation are fully warranted.…”