Combination of the Deacetylase Inhibitor Panobinostat and the Multi-Kinase Inhibitor Sorafenib for the Treatment of Metastatic Hepatocellular Carcinoma - Review of the Underlying Molecular Mechanisms and First Case Report

Advanced hepatocellular carcinoma still represents an unmet medical need that has only a limited overall survival despite the introduction of the multi-kinase inhibitor sorafenib. Recently, inhibitors of histone and other protein deacetylases have been established as novel therapeutic approaches to cancer diseases. We here review the molecular rationale for combining these two novel targeted therapies and report a patient with metastasized hepatocellular carcinoma who showed a partial remission of primary and metastatic lesions for five months after a combination therapy with sorafenib and the orally available pan-deacetylase inhibitor panobinostat

Additive antitumour response to the rabbit VX2 hepatoma by combined radio frequency ablation and toll like receptor 9 stimulation

Introduction: Radiofrequency ablation (RFA), a palliative therapeutic option for solid hepatic tumours, stimulates localised and systemic antitumour cytotoxic T cells. We studied how far addition of CpG B oligonucleotides, toll like receptor (TLR) 9 agonists, would increase the antitumoural T cell response of RFA in the highly aggressive VX2 hepatoma. Methods: Rabbits were randomised to receive RFA, CpG B, their combination or no therapy. The antitumour efficacy of RFA alone or in combination with CpG B was further tested by rechallenging a separate group with intravenously injected VX2 tumour cells after 120 days. Animals were assessed for survival, tumour size and spread, and tumour and immune related histological markers after 120 days. Peripheral blood mononuclear cells were tested for tumour-specific T cell activation and cytotoxicity. Immune modulatory cytokines tumour necrosis factor α, interleukin (IL)-2/IL-8/IL-10/IL-12 and interferon γ, and vascular endothelial growth factor were measured in serum. Results: Mean survival of untreated animals was 36 days, as compared with 97, 78 and 114 days for RFA, CpG and combination therapy, respectively. Compared with untreated controls, antitumour T cell stimulation/cytotoxicity increased 26/16-fold, 32/17-fold and 50/38-fold 2 weeks after RFA, CpG and combination treatments, respectively. The combination inhibited tumour spread to lungs and peritoneum significantly and prohibited new tumour growth in animals receiving a secondary systemic tumour cell injection. RFA alone induced a Th1 cytokine pattern, while IL-8 and IL-10 were only upregulated in CpG treated animals and controls. Conclusions: The combination of TLR9 stimulation with RFA resulted in a potentiated antitumour T cell response and cytotoxicity in the VX2 tumour model. Only this combination prevented subsequent tumour spread and resulted in a significantly improved survival, justifying the need for further exploration of the combination of ablative therapies and TLR9 agonists in liver cancer

Cannabinoid Receptor Type I Modulates Alcohol-Induced Liver Fibrosis

The cannabinoid system (CS) is implicated in the regulation of hepatic fibrosis, steatosis and inflammation, with cannabinoid receptors 1 and 2 (CB1 and CB2) being involved in regulation of pro- and antifibrogenic effects. Daily cannabis smoking is an independent risk factor for the progression of fibrosis in chronic hepatitis C and a mediator of experimental alcoholic steatosis. However, the role and function of CS in alcoholic liver fibrosis (ALF) is unknown so far. Thus, human liver samples from patients with alcoholic liver disease (ALD) were collected for analysis of CB1 expression. In vitro, hepatic stellate cells (HSC) underwent treatment with acetaldehyde, H2O2, endo- and exocannabinoids (2-arachidonoylglycerol (2-AG) and Δ9-tetrahydrocannabinol [THC]), and CB1 antagonist SR141716 (rimonabant). In vivo, CB1 knockout (KO) mice received thioacetamide (TAA)/ethanol (EtOH) to induce fibrosis. As a result, in human ALD, CB1 expression was restricted to areas with advanced fibrosis only. In vitro, acetaldehyde, H2O2, as well as 2-AG and THC, alone or in combination with acetaldehyde, induced CB1 mRNA expression, whereas CB1 blockage with SR141716 dose-dependently inhibited HSC proliferation and downregulated mRNA expression of fibrosis-mediated genes PCα1(I), TIMP-1 and MMP-13. This was paralleled by marked cytotoxicity of SR141716 at high doses (5–10 µmol/L). In vivo, CB1 knockout mice showed marked resistance to alcoholic liver fibrosis. In conclusion, CB1 expression is upregulated in human ALF, which is at least in part triggered by acetaldehyde (AA) and oxidative stress. Inhibition of CB1 by SR141716, or via genetic knock-out protects against alcoholic-induced fibrosis in vitro and in vivo

Arbor

a40

Role of cannabinoid receptors and RAGE in inflammatory bowel disease

Background: The endocanabinoid system is involved in many inflammatory diseases, such as Crohn’s disease (CD) and ulcerative colitis (UC). The distribution and expression of cannabinoid receptors 1 (CNR1) and 2 (CNR2) in combination with inflammatory cytokines and RAGE (receptor of advanced glycation end products), which is also overactive in these diseases, in dependency of the extent of inflammation and alteration of the colon barrier is still unclear and needs to be elucidated. Material and Methods: 10 specimens of CD patients who underwent colectomy and 14 colectomy specimens of patients suffering from UC were investigated histologically for inflammatory infiltrate, extent of fibrosis and for disturbance of the intestinal barrier. Immunohistochemistry was carried out to examine the distribution and localization of CNR1, CNR2 and RAGE. Additionally, qRT-PCR was performed to study the expression of CNR1, CNR2, RAGE and inflammatory cytokines (TNFα, TGFß, CTGF, IL12, IFNγ). 35 morphological and histological normal specimens of colectomy cases served as controls. Results: The expression level of CNR2 did not differ between the control group and the group of patients with IBD, while CNR1 displayed a significant up regulation, especially in cases of CD. A differential association between the expression of CNR1/CNR2 and RAGE with morphological changes and expression of molecular markers of inflammation could be established. Conclusion: We showed that cannabinoid receptors are expressed differentially in inflammatory bowel disease and that the expression seems to be influenced by the underlying disease and by localized inflammation

Sustained treatment response of metastatic hepatocellular carcinoma with bevacizumab and sorafenib

The overall survival for patients with advanced hepatocellular carcinoma (HCC) is still limited. Although the multi-kinase inhibitor sorafenib has recently been approved for this disease, response rates are still low and patients often face dose-limiting toxicities which lead to a reduction in prognosis and treatment success. We here report a patient with metastasized HCC who shows a sustained response for more than 30 mo to sorafenib therapy after failure of a first line therapy with gemcitabine, oxaliplatin and bevacizumab