The Development of Targeted Therapies for Hepatocellular Cancer

Chattopadhyay, Dhrubajyoti; Manas, Derek; Reeves, Helen L.

doi:10.2174/138161207782360717

Cited by 7 publications

(5 citation statements)

References 59 publications

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“…This study highlights the limitations of the current prognostic system, even after correction for the response to treatment. Our findings support a growing body of literature that emphasizes the variable biological nature of individual hepatomas24‐28 and calls for further efforts to find superior biological predictors. Genomic and proteomic advances in the field have further defined the natural history of HCC and will aid in pretransplant and posttransplant prognostication 28.…”

Section: Discussionsupporting

confidence: 82%

Prediction of progression-free survival in patients presenting with hepatocellular carcinoma within the Milan criteria

et al. 2010

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Transplantation is the treatment of choice for hepatocellular carcinoma (HCC) meeting the Milan criteria. HCC and chronic liver diseases have distinct natural histories for which an equitable transplant policy must account. We enrolled and prospectively followed at a single center 206 consecutive HCC patients that presented within the Milan criteria. Patients were treated per the Barcelona Clinic Liver Cancer (BCLC) algorithm; 95% received resection, ablation, or transarterial chemoembolization. The median follow-up was 16 months. Progression occurred in 84 patients, and 8 patients died. Risk factors for the time to disease progression (death or progression beyond T2) were analyzed in 170 patients with a complete data set. Risk factors with the strongest relationship to progression included tumor diameter and tumor persistence/recurrence after local therapy (hazard ratios of 1.51 and 2.75, respectively, when transplanted patients were censored at the time of transplantation and hazard ratios of 1.53 and 3.66, respectively, when transplantation was counted as an event; P 0.0001). To evaluate the current Model for End-Stage Liver Disease (MELD) exception, we compared the expected progression rate (PR) with our observed PR in 133 stage T2 patients. The current policy resulted in a large overestimation of the PR for T2 HCC and an unsatisfactory performance [Harrell's concordance index (C index) ¼ 0.60, transplant censored; C index ¼ 0.55, transplant as progression]. Risk factors for progression that were identified by univariate analysis were considered for multivariate analysis. With these risk factors and the patients' natural MELD scores, an adjusted model applicable to organ allocation was generated, and this decreased the discrepancy between the expected and observed PRs (C index ¼ 0.66, transplant censored; C index ¼ 0.69, transplant as progression). In conclusion, the current MELD exception largely overestimates progression in T2 patients treated according to the BCLC guidelines. The tumor response to resective or ablative treatment can predict tumor progression beyond the Milan criteria, and it should be taken into account in models designed to prioritize organ allocation. Liver Transpl 16:503-512,

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Section: Discussionsupporting

confidence: 82%

Prediction of progression-free survival in patients presenting with hepatocellular carcinoma within the Milan criteria

et al. 2010

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“…IFNα has also been proposed both in the prevention and treatment of HCC (Chattopadhyay et al , 2007). Although the impact of IFN-based therapies to prevent HCC development in cirrhotic patients is still highly controversial (Craxì and Cammà, 2005; Shiratori et al , 2005; Lok et al , 2009), recent studies have shown clinical efficacy of IFNα alone and in combination with chemotherapeutic agents in the treatment of advanced HCCs with portal vein tumor thrombosis and/or extrahepatic metastasis (Obi et al , 2006; Uka et al , 2008).…”

Section: Introductionmentioning

confidence: 99%

p53-paralog DNp73 oncogene is repressed by IFNα/STAT2 through the recruitment of the Ezh2 polycomb group transcriptional repressor

et al. 2011

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The DNp73 proteins act as trans-repressors of p53 and p73-dependent transcription and exert both anti-apoptotic activity and pro-proliferative activity. DNp73s are frequently up-regulated in a variety of human cancers, including human hepatocellular carcinomas (HCCs). Increased levels of DNp73 proteins confer to HCC cells resistance to apoptosis and, irrespective to p53 status, a chemoresistant phenotype. Here, we show that interferon (IFN)α down-regulates DNp73 expression in primary human hepatocytes (PHHs) and HCC cell lines. IFNα has been used as pro-apoptotic agent in the treatment of malignancies and there is increasing evidence of IFNα effectiveness in HCC treatment and prevention of recurrence. The precise mechanisms by which class I IFNs exert their anti-proliferative and anti-tumor activity remain unclear. IFNα binding to its receptor activates multiple intracellular signaling cascades regulating the transcription of numerous direct target genes through the recruitment of a complex comprising of STAT1, STAT2 and IFN regulatory factor (IRF)9 to their promoters. We found that, in response to IFNα, the P2p73 promoter undergoes substantial chromatin remodeling. Histone deacetylases (HDACs) replace histone acetyl transferases. STAT2 is recruited onto the endogenous P2p73 promoter together with the polycomb group protein Ezh2, leading to increased H3K27 methylation and transcriptional repression. The reduction of DNp73 levels by IFNα is paralleled by an increased susceptibility to IFNα-triggered apoptosis of Huh7 hepatoma cells. Our results show, for the first time, that IFN-stimulated gene factor 3 recruitment may serve both in activating and repressing gene expression and identify the down-regulation of DNp73 as an additional mechanism to counteract the chemoresistance of liver cancer cells.

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“…IFNs have been used with varying effectiveness as proapoptotic agents in the treatment of malignancies, as e.g., myeloma (3), renal (4), or bladder cancer (5), and there is increasing evidence of effectiveness of IFNs in the treatment and prevention of HCC. Recent studies show that IFNs, in combination with chemotherapeutics (6) or agents such as proteasome inhibitors (7,8), may prove to be clinically effective. It has been reported that IFN therapy, even after curative treatment of HCC, could prevent HCC recurrence and improve survival.…”

Section: Introductionmentioning

confidence: 99%

IFN-α–Induced Apoptosis in Hepatocellular Carcinoma Involves Promyelocytic Leukemia Protein and TRAIL Independently of p53

et al. 2009

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IFNs are pleiotropic cytokines that have been shown to be important regulators of cell growth. IFN-A has recently been recognized to harbor therapeutic potential in prevention and treatment of hepatocellular carcinoma (HCC). However, HCC cells respond differentially to IFN treatment, the mechanism of which is largely unknown. To address this issue, we analyzed the effect of IFN-A on different liver tumor cell lines. We found that growth inhibiting effects of IFN-A in hepatoma cells require PML-NB induction and, moreover, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression on the mRNA and protein level.

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The Development of Targeted Therapies for Hepatocellular Cancer

Cited by 7 publications

References 59 publications

Prediction of progression-free survival in patients presenting with hepatocellular carcinoma within the Milan criteria

Prediction of progression-free survival in patients presenting with hepatocellular carcinoma within the Milan criteria

p53-paralog DNp73 oncogene is repressed by IFNα/STAT2 through the recruitment of the Ezh2 polycomb group transcriptional repressor

IFN-α–Induced Apoptosis in Hepatocellular Carcinoma Involves Promyelocytic Leukemia Protein and TRAIL Independently of p53

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