Evolution of systemic therapy of advanced hepatocellular carcinoma

Yau, Thomas; Chan, Pierre; Epstein, Richard J.; Poon, Ronnie Tung Ping

doi:10.3748/wjg.14.6437

Cited by 57 publications

(45 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…transcription factor inhibitor | xenograft tumor model | CP2 | TFCP2 H epatocellular carcinoma (HCC) is characterized by late-stage diagnosis and a poor prognosis for treatment, which usually consists of surgical resection of the tumor and chemotherapy (1)(2)(3). Currently, the only approved treatment for primary malignancies is sorafenib, a receptor tyrosine kinase and Raf inhibitor originally developed for primary kidney cancer that is also marginally effective against HCC, increasing survival by 2-3 mo as a single treatment.…”

mentioning

confidence: 99%

Antiproliferative small-molecule inhibitors of transcription factor LSF reveal oncogene addiction to LSF in hepatocellular carcinoma

Grant¹,

Bishop

Christadore

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Despite the prevalence of HCC, there is no effective, systemic treatment. The transcription factor LSF is a promising protein target for chemotherapy; it is highly expressed in HCC patient samples and cell lines, and promotes oncogenesis in rodent xenograft models of HCC. Here, we identify small molecules that effectively inhibit LSF cellular activity. The lead compound, factor quinolinone inhibitor 1 (FQI1), inhibits LSF DNA-binding activity both in vitro, as determined by electrophoretic mobility shift assays, and in cells, as determined by ChIP. Consistent with such inhibition, FQI1 eliminates transcriptional stimulation of LSF-dependent reporter constructs. FQI1 also exhibits antiproliferative activity in multiple cell lines. In LSF-overexpressing cells, including HCC cells, cell death is rapidly induced; however, primary or immortalized hepatocytes are unaffected by treatment with FQI1. The highly concordant structure–activity relationship of a panel of 23 quinolinones strongly suggests that the growth inhibitory activity is due to a single biological target or family. Coupled with the striking agreement between the concentrations required for antiproliferative activity (GI 50 s) and for inhibition of LSF transactivation (IC 50 s), we conclude that LSF is the specific biological target of FQIs. Based on these in vitro results, we tested the efficacy of FQI1 in inhibiting HCC tumor growth in a mouse xenograft model. As a single agent, tumor growth was dramatically inhibited with no observable general tissue cytotoxicity. These findings support the further development of LSF inhibitors for cancer chemotherapy.

show abstract

mentioning

confidence: 99%

Antiproliferative small-molecule inhibitors of transcription factor LSF reveal oncogene addiction to LSF in hepatocellular carcinoma

Grant¹,

Bishop

Christadore

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Systemic chemotherapy has been adopted to treat advanced patients with hepatocellular carcinoma for more than 30 years, but the survival outcome of these patients remained unsatisfactory (3,4). The emergence of targeted therapy, encouraged by improved survival benefits from sorafenib, will become a major strategy for treatment of advanced patients with hepatocellular carcinoma.…”

Section: Discussionmentioning

confidence: 99%

“…Up to 70% of patients with hepatocellular carcinoma have been suffering from limited treatment options because of late diagnosis and/or advanced stage of the disease when, however, surgical treatments including liver transplantation and hepatectomy as well as regional therapy are not feasible. Currently, there is no proven effective conventional systemic chemotherapy for patients with advanced hepatocellular carcinoma because of the inherent chemoresistant nature of hepatocellular carcinoma and with intolerable cytotoxicity, resulting in the dismal prognosis of these patients (2)(3)(4). Hepatocellular carcinoma is a heterogeneous disease in terms of etiology, molecular, and carcinogenic mechanisms as well as biologic behaviors, which can collectively contribute to diverse mechanisms of chemoresistance among patients with hepatocellular carcinoma (5).…”

Section: Introductionmentioning

confidence: 99%

Identification of Transmembrane Protein 98 as a Novel Chemoresistance-Conferring Gene in Hepatocellular Carcinoma

Guo

et al. 2014

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Chemoresistance is one of the major obstacles in systemic chemotherapy and targeted therapy for patients with advanced hepatocellular carcinoma. To identify novel chemoresistance-associated targets in hepatocellular carcinoma, chemoresistant hepatocellular carcinoma cell lines were established. By comparing the global gene expression profiles between chemoresistant and chemosensitive cell lines, eight novel chemoresistance-associated genes were identified to be significantly associated with the commonly augmented chemoresistance of hepatocellular carcinoma cells. One upregulated candidate named transmembrane protein 98 (TMEM98) was found to be overexpressed in 80 of 118 (67.80%) of patients with hepatocellular carcinoma. TMEM98 mRNA in tumor tissues was significantly higher than nontumor tissues of patients with hepatocellular carcinoma (P < 0.0001). Upregulation of TMEM98 was significantly correlated with advanced tumor stage (P ¼ 0.048), high incidence of early tumor recurrence (P ¼ 0.005), poor overall survival (P ¼ 0.029), and poor disease-free survival (P ¼ 0.011) of patients with hepatocellular carcinoma after hepatectomy. Importantly, upregulation of TMEM98 mRNA in patients with hepatocellular carcinoma who received transarterial chemoembolization (TACE) treatment was significantly higher than in patients without TACE treatment (P ¼ 0.046). Moreover, patients with poor response to TACE treatment had higher degree of TMEM98 upregulation than the responsive patients. In vitro and in vivo studies showed that suppression of TMEM98 in chemoresistant hepatocellular carcinoma cells restored their chemosensitivity, while forced overexpression of TMEM98 enhanced their chemoresistance. The mechanism of TMEM98 in conferring chemoresistance of hepatocellular carcinoma might be possibly through activation of the AKT pathway and deactivation of p53. In conclusion, we identified a panel of novel common chemoresistance-associated genes and demonstrated that TMEM98 is a chemoresistanceconferring gene in hepatocellular carcinoma. Mol Cancer Ther; 13(5); 1285-97. Ó2014 AACR.

show abstract

“…Surgical, local ablative, chemotherapy options are currently available for HCC treatment. Recently, there has been a growing interest in the therapeutic use of natural products for liver carcinoma [7], because systemic chemotherapy has been unsuccessful in the studies thus far [8].…”

Section: Introductionmentioning

confidence: 99%

Correlation and Multiple Regression Analyses of Pituitary Growth Hormone and Hepatic Activities in Hepatitis C Infection and Interferon Response

et al. 2013

View full text Add to dashboard Cite

The prevalence of hepatitis C virus (HCV) infection varies across the world, with the highest percent of infections reported in Middle East, increasingly in Egypt. The current study aimed at examining the bio-statistical correlation and multiple regression analyses of pituitary growth hormone (GH) and liver activities among HCV genotype-4 patients treated with PEG-IFN-a plus RBV therapy. Herein, the current study was conducted on 100 HCV genotype-4 infected patients and 50 healthy controls. Patients received PEG-IFN-a/RBV for 24 weeks. Host RNA was isolated from patients' sera for HCV genotyping and viral load determination. Moreover, the enzymatic activities of the liver, AFP, GH, PT, and CBC were performed in all volunteers. The present study resulted that the activities of the hepatic enzymes among HCV genotype-4 patients correlated together significantly. While, human GH showed a significant positive regression with pre-treatment ALT concentration in responders. Furthermore, multiple regression analysis for GH showed a significant positive correlation with pre-treatment ALT in HCV genotype-4 infected patients. We concluded that there were a putative significant relation between GH and pre-treatment ALT activity in HCV infection and response to IFN-based therapy.

show abstract

Evolution of systemic therapy of advanced hepatocellular carcinoma

Cited by 57 publications

References 46 publications

Antiproliferative small-molecule inhibitors of transcription factor LSF reveal oncogene addiction to LSF in hepatocellular carcinoma

Antiproliferative small-molecule inhibitors of transcription factor LSF reveal oncogene addiction to LSF in hepatocellular carcinoma

Identification of Transmembrane Protein 98 as a Novel Chemoresistance-Conferring Gene in Hepatocellular Carcinoma

Correlation and Multiple Regression Analyses of Pituitary Growth Hormone and Hepatic Activities in Hepatitis C Infection and Interferon Response

Contact Info

Product

Resources

About