The present and the future landscape of treatment of advanced hepatocellular carcinoma

Rimassa, Lorenza; Santoro, Armando

doi:10.1016/s1590-8658(10)60516-6

Cited by 22 publications

(13 citation statements)

References 37 publications

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“…Risk factors associated with HCC are well documented, but usually prognosis is negative due to high malignancy of the lesion once diagnosed, and lack of effective therapies [14]. All these facts mean that only 30-40% of patients are suitable for curative treatments, generally corresponding to liver resection or transplantation [15]. For these reasons, the discovery of new treatments to expand the present therapeutic options is essential in the future handling of the disease.…”

Section: Discussionmentioning

confidence: 99%

The NADPH oxidase inhibitor VAS2870 impairs cell growth and enhances TGF-β-induced apoptosis of liver tumor cells

Sancho

Fabregat

2011

Biochemical Pharmacology

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This compound inhibits dose-dependently autocrine increase of cell number in FaO rat hepatoma cells, and almost completely blocked ROS production and thymidine incorporation when used at 25 M. Such inhibitory effect on autocrine growth is coincident with lower mRNA levels of EGFR (Epidermal Growth Factor Receptor) and its ligand TGF-(Transforming Growth Factor-alpha), and decreased phosphorylation of the EGFR itself and other downstream targets, such as SRC or AKT. Moreover, NADPH oxidase pharmacological inhibition also effectively attenuates serum-dependent growth and phosphorylation of AKT and ERK. Importantly, these inhibitory effects on either autocrine or serum-dependent cell growth are observed in several human HCC cell lines. Finally, we have observed that VAS2870 is also effective in enhancing apoptosis induced by a physiological stimulus, such as TGF-. In summary, NADPH oxidase pharmacological inhibition could be considered a promising tool in the treatment of liver cancer.

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Section: Discussionmentioning

confidence: 99%

The NADPH oxidase inhibitor VAS2870 impairs cell growth and enhances TGF-β-induced apoptosis of liver tumor cells

Sancho

Fabregat

2011

Biochemical Pharmacology

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“…In a phase II trial this agent was well-tolerated and the OS was 9.1 months. Of note, one complete response was observes in a Sorafenibrefractory patient and one partial response in a cirrhotic Child-Pugh B patient (Rimassa & Santoro 2010).…”

Section: Ngr-htnfmentioning

confidence: 92%

“…The results of SHARP trial was a milestone in the treatment of HCC and stimulated the search for similar compounds targeting other molecular alterations, in particular because combination treatments are postulated to be a promising approach through synergistic antitumoral effects (Rimassa & Santoro, 2010) 3.The future trends…”

Section: Systemic Therapy For Advanced-stage Hccmentioning

confidence: 99%

Future Trends in the Management of Advanced Hepatocellular Carcinoma (HCC)

Dimitroulopoulos¹,

Fotopoulou²

2012

Hepatocellular Carcinoma - Clinical Research

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“…No therapeutically beneficial drug in advanced inoperable HCC was available until 2007 (9). It came as a breakthrough discovery in the field when sorafenib improved overall survival (OS) in advanced HCC patients in a phase II randomized placebo-controlled trial (14). Subsequently two phase III randomized double-blind placebocontrolled trials were conducted.…”

Section: Hccmentioning

confidence: 99%

“…Subsequently two phase III randomized double-blind placebocontrolled trials were conducted. The SHARP trial evaluated 602 patients with advanced HCC who had not received prior systemic therapy, to receive either sorafenib or placebo with the primary endpoint being OS (14). The median OS was significantly longer in the sorafenib group than in the placebo group (10.7 vs. 7.9 months; P<0.001).…”

Section: Hccmentioning

confidence: 99%

Molecular targeted therapies for cancer: Sorafenib monoï¿½therapy and its combination with other therapies (Review)

Ibrahim

Walsh

et al. 2012

Oncol Rep

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Abstract. Sorafenib is an oral multikinase inhibitor that acts by inhibiting tumor growth and disrupting tumor microvasculature through antiproliferative, anti-angiogenic and proapoptotic effects. It exerts these effects via inhibition of multiple targets including Raf serine/threonine kinases, vascular endothelial growth factor receptor tyrosine kinases; VEGFR-1, VEGFR-2, VEGFR-3 and platelet-derived growth factor receptor β (PDGFR-β). Current literature shows that the deregulated signaling through these receptors is commonly seen in human tumors. In addition, sorafenib is also shown to induce apoptosis through downregulation of Mcl-1 in many cancer types. Hence, sorafenib as a single agent has shown promising activity in some cancers such as renal cell carcinoma (RCC), hepatocellular carcinoma (HCC) and thyroid cancers. Currently, the drug holds FDA approval for the treatment of advanced RCC and unresectable HCC. However, many clinical studies have indicated several limitations to the application of sorafenib as a single agent in various other cancers. Owing to these reasons and the potential of sorafenib to synergize with other anticancer therapies, its combination with other targeted agents and chemotherapy has been widely explored with promising results. In addition, it has also shown synergistic results when combined with radiation. This review summarizes the current basic and clinical studies on the effects and mechanisms of sorafenib either administered alone or in combination with other anticancer treatments. IntroductionSince the 1980s, the field of cancer treatment has experienced a major paradigm shift from broad-spectrum cytotoxic chemotherapeutics to the development of targeted therapies tailored to inhibit cancer-specific pathways (1). This change was prompted by the limitations of the treatment mainstays in those days, which were surgery, chemotherapy and radiotherapy. Surgery was limited to early non-metastatic diseases, however, research demonstrates that solid tumors are frequently metastatic at presentation (2). Radiation and chemotherapy has limited capacity to discriminate between cancerous and normal cells and hence, results in severe side effects (3). Furthermore, solid tumors are inherently resistant to both radiation and chemotherapy. Therefore, the rationale for development of molecular targeted therapies was to overcome drug resistance, to make malignant cells more susceptible to suppression and damage whilst avoiding substantial toxicity to the rest of the body tissues and also to provide a higher therapeutic index.The molecular targeted therapies include monoclonal antibodies, tyrosine kinase inhibitors, rapamycin pathway inhibitors, proteasome inhibitors and inhibitors of Raf kinase (4). Many of these drugs have shown therapeutic benefit in various cancers, however, several challenges are yet to be conquered by the developers. These include overcoming certain amount of acquired resistance in cancer cells, selecting suitable dosage schedules, determining the stage to start treatmen...

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The present and the future landscape of treatment of advanced hepatocellular carcinoma

Cited by 22 publications

References 37 publications

The NADPH oxidase inhibitor VAS2870 impairs cell growth and enhances TGF-β-induced apoptosis of liver tumor cells

The NADPH oxidase inhibitor VAS2870 impairs cell growth and enhances TGF-β-induced apoptosis of liver tumor cells

Future Trends in the Management of Advanced Hepatocellular Carcinoma (HCC)

Molecular targeted therapies for cancer: Sorafenib monoï¿½therapy and its combination with other therapies (Review)

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