Molecular Therapies in Hepatocellular Carcinoma: What Can We Target?

Galuppo, Roberto; Ramaiah, Dinesh; Ponte, Oscar Moreno; Gedaly, Roberto

doi:10.1007/s10620-014-3058-x

Cited by 39 publications

(35 citation statements)

References 61 publications

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“…To date, there is no effective treatment for HCC, and the lack of effective diagnostic techniques available, due to the undefined etiology and pathogenesis and high-grade malignancy, contributes to poor patient prognosis (2). Ascertaining the origin and development of liver cancer and identification of novel targets for therapy have been the focus of recent studies regarding HCC (3)(4)(5)(6)(7). MicroRNAs (miRs) are single-stranded noncoding RNAs, containing 17-19 nucleotides, which are associated with the development and progression of tumors (8)(9)(10)(11)(12) such as oropharyngeal squamous cell carcinoma (8), non-small cell lung cancer (9), thyroid cancer (10).…”

Section: Introductionmentioning

confidence: 99%

miR-125a inhibits the migration and invasion of liver cancer cells via suppression of the PI3K/AKT/mTOR signaling pathway

Tang

Liang

et al. 2015

Oncology Letters

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Abstract. In order to explore the regulation of the invasive ability of hepatocellular carcinoma cells and the underlying mechanism, mimics sequences of microRNA (miR)-125a (miR-125a-3p/5p) and scramble sequences (miR-125a-3p-s/5p-s) were transfected into human hepatocellular carcinoma cell lines, HCC-LM3 and HepG2, and the non-malignant epithelioid hepatic cell line QZG. To inhibit and upregulate the expression of miR-125a individually. Protein expression was detected by western blotting, and the cell proliferation and migration abilities were evaluated by soft agar colony formation and Transwell assay, respectively. It was revealed that the expression of miR-125a was downregulated in HepG2 and HCC-LM3 cells compared with that of QZG cells, and expression was markedly lower in HCC-LM3 cells than that in HepG2 cells (P<0.01). The colony formation and migration rates of the cells transfected with miR-125a-3p/5p were decreased compared with negative controls, but were increased in cells transfected with miR-125a-3p-3/5p-s (P<0.01). The protein and messenger RNA expression of phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) was decreased following transfection with miR-125a-5p, whereas expression was increased compared with negative controls following transfection with miR-125a-5p-s (P<0.01). Furthermore, the proliferation and migration abilities of cells were attenuated following inhibition of the PI3K/AKT/mTOR pathway by LY294002. The results of the present study indicated that miR-125a inhibits the invasive ability of hepatocellular carcinoma cells via regulation of the PI3K/AKT/mTOR pathway.

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Section: Introductionmentioning

confidence: 99%

miR-125a inhibits the migration and invasion of liver cancer cells via suppression of the PI3K/AKT/mTOR signaling pathway

Tang

Liang

et al. 2015

Oncology Letters

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“…Sorafenib also decreases the level of hypoxia inducible factor-1α and VEGF A expression, which normally promote the progression of residual tumors after RFA [73]. There are also several new potential molecular target agents (e.g., lenvatinib, tivantinib, etc) for patients with HCC [74,75]. However, the exact role of these agents in combination treatment with tumor ablation warrants further evaluation, as in the recently completed STORM trial (NCT00692770), which failed to demonstrate an advantage of using sorafenib in preventing recurrence after local ablation or surgical resection.…”

Section: Advances In Combined Treatment With Tumor Ablationmentioning

confidence: 99%

Recent Advances in Tumor Ablation for Hepatocellular Carcinoma

2015

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Image-guided tumor ablation for early stage hepatocellular carcinoma (HCC) is an accepted non-surgical treatment that provides excellent local tumor control and favorable survival benefit. This review summarizes the recent advances in tumor ablation for HCC. Diagnostic imaging and molecular biology of HCC has recently undergone marked improvements. Second-generation ultrasonography (US) contrast agents, new computed tomography (CT) techniques, and liver-specific contrast agents for magnetic resonance imaging (MRI) have enabled the early detection of smaller and inconspicuous HCC lesions. Various imaging-guidance tools that incorporate imaging-fusion between real-time US and CT/MRI, that are now common for percutaneous tumor ablation, have increased operator confidence in the accurate targeting of technically difficult tumors. In addition to radiofrequency ablation (RFA), various therapeutic modalities including microwave ablation, irreversible electroporation, and high-intensity focused ultrasound ablation have attracted attention as alternative energy sources for effective locoregional treatment of HCC. In addition, combined treatment with RFA and chemoembolization or molecular agents may be able to overcome the limitation of advanced or large tumors. Finally, understanding of the biological mechanisms and advances in therapy associated with tumor ablation will be important for successful tumor control. All these advances in tumor ablation for HCC will result in significant improvement in the prognosis of HCC patients. In this review, we primarily focus on recent advances in molecular tumor biology, diagnosis, imaging-guidance tools, and therapeutic modalities, and refer to the current status and future perspectives for tumor ablation for HCC.

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“…Advanced hepatocellular carcinoma (aHCC) is a complex disease characterized by molecular heterogeneity and underlying liver dysfunction attributable to the frequent presence of chronic liver disease, often at the stage of cirrhosis [3][4][5]. The complexity of HCC is underscored by multiple signaling pathways involved in its pathogenesis, matched by the many drugs tested against ligands, receptors, and/or downstream signaling molecules in these pathways [6][7][8][9][10][11][12]5]. These include inhibitors of vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), Ras/Raf/mitogen-extracellular activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK), mammalian target of rapamycin (mTOR), and c-MET [6][7][8][9][10][11][12]5] (Fig.…”

Section: Introductionmentioning

confidence: 99%

“…Many targeted drugs and combinations have been tested in HCC, with upwards of 55 drugs currently in phase 1-3 trials [10]. Despite the emergence of new targeted therapies for HCC, toxicity remains a concern, often leading to trial discontinuation.…”

Section: Introductionmentioning

confidence: 99%

Evaluating the role of treatment-related toxicities in the challenges facing targeted therapies for advanced hepatocellular carcinoma

Palmer

Johnson

2015

Cancer Metastasis Rev

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Advanced hepatocellular carcinoma (aHCC) is a complex disease beset by underlying liver dysfunction and high molecular heterogeneity. Sorafenib, introduced in 2007, is considered the standard systemic therapy for aHCC, yet only a minority of patients show objective evidence of a response radiologically, and median overall survival is still under 1 year. Other targeted drugs for the treatment of aHCC have failed to reach their primary endpoints of improved/non-inferior overall survival in comparison with sorafenib in recent phase 3 trials. Toxicity was a significant problem, raising the question as to whether outcomes in aHCC trials are being hindered by high levels of adverse events (AEs), particularly in populations with underlying cirrhosis. This is true of six recently failed phase 3 studies involving sunitinib, erlotinib, linifanib, brivanib (two trials), and everolimus, as well as ongoing phase 2 and 3 trials of other drugs that work through similar molecular pathways. This article reviews these drugs' toxicities, with a focus on AEs as a reason for their failure in phase 3 trials of patients with aHCC. We also review completed and ongoing phase 3 studies of combination therapies with sorafenib, as well as toxicities of many of the targeted agents in aHCC, including geographic/ethnic differences, measures of toxicity, and strategies to improve management.

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Molecular Therapies in Hepatocellular Carcinoma: What Can We Target?

Cited by 39 publications

References 61 publications

miR-125a inhibits the migration and invasion of liver cancer cells via suppression of the PI3K/AKT/mTOR signaling pathway

miR-125a inhibits the migration and invasion of liver cancer cells via suppression of the PI3K/AKT/mTOR signaling pathway

Recent Advances in Tumor Ablation for Hepatocellular Carcinoma

Evaluating the role of treatment-related toxicities in the challenges facing targeted therapies for advanced hepatocellular carcinoma

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