Systemic treatments for hepatocellular carcinoma: challenges and future perspectives

Tovoli, Francesco; Negrini, Giulia; Benevento, Francesca; Faggiano, Chiara; Goio, Elisabetta; Granito, Alessandro

doi:10.2217/hep-2017-0020

Cited by 31 publications

(27 citation statements)

References 84 publications

(81 reference statements)

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“…In fact, the possibility of combined HCC-CC appearing as a typical HCC has been reported. This scenario will likely change in the next years as the need for liver biopsies will likely increase due to the increasing number of clinical trials and therapeutic options requiring the identification of biomarkers [76]. Therefore, an increase in the number of identified combined HCC-CC is also likely.…”

Section: Discussionmentioning

confidence: 99%

Treatment of Combined Hepatocellular and Cholangiocarcinoma

Leoni

Sansone

Lorenzo

et al. 2020

Cancers

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Combined hepatocellular and cholangiocarcinoma (HCC-CC) is a rare primary liver cancer. It is constituted by neoplastic cells of both hepatocellular and cholangiocellular derivation. Different histology types of HCC-CC have been reported, hinting at heterogeneous carcinogenic pathways leading to the development of this cancer. Due to its rarity and complexity, mixed HCC-CC is a scantly investigated condition with unmet needs and unsatisfactory outcomes. Surgery remains the preferred treatment in resectable patients. The risk of recurrence, however, is high, especially in comparison with other primary liver cancers such as hepatocellular carcinoma. In unresectable or recurring patients, the therapeutic options are challenging due to the dual nature of the neoplastic cells. Consequently, the odds of survival of patients with HCC-CC remains poor. We analysed the literature systematically about the treatment of mixed HCC-CC, reviewing the main therapeutic options and their outcomes and analysing the most interesting developments in this topic with a focus on new potential therapeutic avenues.

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Section: Discussionmentioning

confidence: 99%

Treatment of Combined Hepatocellular and Cholangiocarcinoma

Leoni

Sansone

Lorenzo

et al. 2020

Cancers

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“…To elucidate the potential mechanisms underlying the AMPK effect on stem-like cells, we analysed some of the signalling pathways associated with development and differentiation in HCC cells transfected with AMPK. Previous studies have reported that the Wnt/ b-catenin signalling pathway is associated with the control of stem cell differentiation (Valkenburg et al, 2011). The activation of this pathway causes the accumulation of b-catenin in the cytosol, which is translocated to the nucleus, where it binds to LEF/ TCF transcription factors and regulates the expression of target genes, including genes involved in differentiation and the cell cycle.…”

Section: Potential Mechanisms Involved In the Ampk Effectmentioning

confidence: 99%

“…The prognosis for patients with advanced HCC remains extremely poor due to the high resistance to cytotoxic therapy. For the past decade, the multikinase inhibitor sorafenib has been the only approved standard treatment for patients with advanced HCC (Kudo, 2017), albeit it only extends life expectancy by 2-3 months (Cheng et al, 2009;Llovet et al, 2008;Tovoli et al, 2018). This can be attributed to the acquisition of resistance, predominantly due to the upregulation of certain survival pathways that may cover up the death signals induced by sorafenib (Zhu et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Targeting AMP‐activated kinase impacts hepatocellular cancer stem cells induced by long‐term treatment with sorafenib

et al. 2019

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Hepatocellular carcinoma ( HCC ) is the third leading cause of cancer death worldwide. HCC treatment is hindered by the frequent emergence of chemoresistance to the multikinase inhibitor sorafenib, which has been related to the presence of cancer stem cells ( CSC s) that self‐renew and often escape therapy. The key metabolic sensor AMP ‐activated kinase ( AMPK ) has recently been recognized as a tumour growth regulator. In this study, we aimed to elucidate the role of AMPK in the development of a stem cell phenotype in HCC cells. To this end, we enriched the CSC population in HCC cell lines that showed increased expression of drug resistance ( ALDH 1A1, ABCB 1A) and stem cell ( CD 133, Nanog, Oct4, alpha fetoprotein) markers and demonstrated their stemness phenotype. These cells were refractory to sorafenib‐induced cell death. We report that sorafenib‐resistant cells had lower levels of total and phosphorylated AMPK as well as its downstream substrate, ACC , compared with the parental cells. Interestingly, AMPK knockdown with si RNA or inhibition with dorsomorphin increased the expression of stem cell markers in parental cells and blocked sorafenib‐induced cell death. Conversely, the upregulation of AMPK , either by transfection or by pharmacological activation with A‐769662, decreased the expression of ALDH 1A1, ABCB 1A, CD 133, Nanog, Oct4, and alpha fetoprotein, and restored sensitivity to sorafenib. Analysis of the underlying mechanism points to hypoxia‐inducible factor HIF ‐1α as a regulator of stemness. In vivo studies in a xenograft mouse model demonstrated that stem‐like cells have greater tumourigenic capacity. AMPK activation reduced xenograft tumour growth and decreased the expression of stem cell markers. Taken together, these results indicate that AMPK may serve as a novel target to overcome chemoresistance in HCC .

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“…According to the BCLC algorithm, the treatment of patients with stage C HCC is systemic sorafenib therapy (33). At present, systemic treatment of HCC is evolving rapidly, and three new multikinase inhibitors (i.e., regorafenib, lenvatinib, and cabozantinib) have been shown to be effective in phase 3 clinical trials (34). In the REFLECT trial, lenvatinib has shown to be non-inferior to sorafenib in a front-line setting (35).…”

Section: Advanced-stage Diseasementioning

confidence: 99%

Current Topics and Perspectives in Surgical Management of Hepatocellular Carcinoma

Lünse

Heidecke

Partecke

2019

Hepatocellular Carcinoma

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Hepatocellular carcinoma is among the leading causes of cancer-related mortality. Due to the numerous surgical and non-surgical therapeutic options, the treatment strategy requires an optimal selection of patients based on tumor stage and liver functional reserve. A potentially curative surgical resection or liver transplantation is only recommended for patients with early stage disease. In this chapter, we overview the current topics and perspectives in the surgical management of hepatocellular carcinoma by disease stage with a special focus on new surgical techniques and expanding range of indications outside of the accepted Barcelona Clinic Liver Cancer algorithm.

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Systemic treatments for hepatocellular carcinoma: challenges and future perspectives

Cited by 31 publications

References 84 publications

Treatment of Combined Hepatocellular and Cholangiocarcinoma

Treatment of Combined Hepatocellular and Cholangiocarcinoma

Targeting AMP‐activated kinase impacts hepatocellular cancer stem cells induced by long‐term treatment with sorafenib

Current Topics and Perspectives in Surgical Management of Hepatocellular Carcinoma

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