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Montella L, Sarno F, Ambrosino A, Facchini S, D’Antò M, Laterza MM, Fasano M, Quarata E, Ranucci RAN, Altucci L, Berretta M, Facchini G. The Role of Immunotherapy in a Tolerogenic Environment: Current and Future Perspectives for Hepatocellular Carcinoma. Cells 2021; 10:1909. [PMID: 34440678 PMCID: PMC8393830 DOI: 10.3390/cells10081909] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 07/22/2021] [Accepted: 07/23/2021] [Indexed: 12/11/2022] Open
Abstract
In contrast to several tumors whose prognoses are radically affected by novel immunotherapeutic approaches and/or targeted therapies, the outcomes of advanced hepatocellular carcinoma (HCC) remain poor. The underlying cirrhosis that is frequently associated with it complicates medical treatment and often determines survival. The landscape of HCC treatment had included sorafenib as the only drug available for ten years, until 2018, when lenvatinib was approved for treatment. The second-line systemic treatments available for hepatocellular carcinoma include regorafenib, cabozantinib, ramucirumab, and, more recently, immune checkpoint inhibitors. However, the median survival remains below 15 months. The results obtained in clinics should be interpreted whilst considering the peculiar role of the liver as an immune organ. A healthy liver microenvironment ordinarily experiences stimulation by gut-derived antigens. This setup elucidates the response to chronic inflammation and the altered balance between tolerance and immune response in HCC development. This paper provides an overview of the mechanisms involved in HCC pathogenesis, with a special focus on the immune implications, along with current and future clinical perspectives.
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Affiliation(s)
- Liliana Montella
- ASL NA2 NORD, Oncology Operative Unit, “Santa Maria delle Grazie” Hospital, 80078 Pozzuoli, Italy; (M.M.L.); (E.Q.)
| | - Federica Sarno
- Precision Medicine Department, “Luigi Vanvitelli” University of Campania, 80138 Naples, Italy; (F.S.); (L.A.)
| | - Annamaria Ambrosino
- ASL NA2 NORD, Internal Medicine Operative Unit, “Santa Maria delle Grazie” Hospital, 80078 Pozzuoli, Italy; (A.A.); (M.D.); (R.A.N.R.)
| | - Sergio Facchini
- Department of Precision Medicine, Division of Medical Oncology, “Luigi Vanvitelli” University of Campania, 80131 Naples, Italy; (S.F.); (M.F.)
| | - Maria D’Antò
- ASL NA2 NORD, Internal Medicine Operative Unit, “Santa Maria delle Grazie” Hospital, 80078 Pozzuoli, Italy; (A.A.); (M.D.); (R.A.N.R.)
| | - Maria Maddalena Laterza
- ASL NA2 NORD, Oncology Operative Unit, “Santa Maria delle Grazie” Hospital, 80078 Pozzuoli, Italy; (M.M.L.); (E.Q.)
| | - Morena Fasano
- Department of Precision Medicine, Division of Medical Oncology, “Luigi Vanvitelli” University of Campania, 80131 Naples, Italy; (S.F.); (M.F.)
| | - Ermelinda Quarata
- ASL NA2 NORD, Oncology Operative Unit, “Santa Maria delle Grazie” Hospital, 80078 Pozzuoli, Italy; (M.M.L.); (E.Q.)
| | - Raffaele Angelo Nicola Ranucci
- ASL NA2 NORD, Internal Medicine Operative Unit, “Santa Maria delle Grazie” Hospital, 80078 Pozzuoli, Italy; (A.A.); (M.D.); (R.A.N.R.)
| | - Lucia Altucci
- Precision Medicine Department, “Luigi Vanvitelli” University of Campania, 80138 Naples, Italy; (F.S.); (L.A.)
| | - Massimiliano Berretta
- Department of Clinical and Experimental Medicine, University of Messina, 98121 Messina, Italy;
| | - Gaetano Facchini
- ASL NA2 NORD, Oncology Operative Unit, “Santa Maria delle Grazie” Hospital, 80078 Pozzuoli, Italy; (M.M.L.); (E.Q.)
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Chang Lee R, Tebbutt N. Systemic treatment of advanced hepatocellular cancer: new hope on the horizon. Expert Rev Anticancer Ther 2019; 19:343-353. [PMID: 30793991 DOI: 10.1080/14737140.2019.1585245] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) is among the leading causes of cancer-related mortality in the world. The majority of the patients present at an advanced or incurable stage where neither locoregional treatment nor combination treatment of locoregional treatment and systemic therapies is feasible. For decades sorafenib was the only treatment option available for advanced HCC. However, with the advent of new and more effective therapies recently, the overall prognosis of advanced HCC has improved significantly. Areas covered: This review summarises the current systemic treatment options available and future prospects in the management of advanced HCC where patients are not suitable for locoregional treatment. Expert opinion: New effective targeted therapeutics have dramatically changed the treatment landscape for advanced HCC. The incorporation of sequential therapy including sorafenib or lenvatinib as first-line treatment and immunotherapy, regorafenib or cabozantinib as second-line treatment have significantly improved outcomes for patients with advanced HCC. Further development of novel combinations of these new agents and predictive/prognostic biomarkers are being explored. Efforts should also be made to tailor treatment to individual patients based on etiology, clinical and molecular factors.
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Affiliation(s)
- Rachael Chang Lee
- a Department of Medical Oncology , Olivia Newton-John Cancer Wellness and Research Centre , Heidelberg , Australia
| | - Niall Tebbutt
- a Department of Medical Oncology , Olivia Newton-John Cancer Wellness and Research Centre , Heidelberg , Australia
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McNamara MG, Slagter AE, Nuttall C, Frizziero M, Pihlak R, Lamarca A, Tariq N, Valle JW, Hubner RA, Knox JJ, Amir E. Sorafenib as first-line therapy in patients with advanced Child-Pugh B hepatocellular carcinoma-a meta-analysis. Eur J Cancer 2018; 105:1-9. [PMID: 30384012 DOI: 10.1016/j.ejca.2018.09.031] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Revised: 09/09/2018] [Accepted: 09/26/2018] [Indexed: 01/10/2023]
Abstract
BACKGROUND Sorafenib has demonstrated survival benefit in first-line treatment of advanced hepatocellular carcinoma (HCC); utility of sorafenib in patients with advanced HCC and Child-Pugh B (CP-B) liver function remains a subject of debate. METHODS A systematic review identified studies using first-line sorafenib in patients with advanced HCC and CP-A/B liver function. Meta-regression analysis comprising linear regression was conducted to explore the association between the baseline factors and overall survival (OS). Differences between efficacy/safety and tolerability parameters were explored using meta-analysis. RESULTS Thirty studies (12 Asian) comprising 8678 patients (August 2002 - September 2012) were included (four randomised controlled trials, 26 cohort studies). Median age was 61 years and 83% were men. Hepatitis B/C status was positive in 35%/22%, respectively. The CP status was available for 8577 patients (99%); CP-A, 79% and CP-B, 19%. Median OS on sorafenib for entire cohort was 7.2 months; 8.8 months in CP-A and 4.6 months in CP-B. Multivariable meta-regression analysis showed significant negative association between OS and proportion of patients with the Eastern Cooperative Oncology Group performance status 2 (P = 0.04) and CP-B liver function (P = 0.001). Among four studies reporting multivariable comparison of the CP status, CP-B was associated with significantly worse OS (P < 0.001). There were no differences in the response rate to sorafenib between patients with CP-A (4.6%) and CP-B (4.2%) liver function. Safety and tolerability were similar; 35% of patients with CP-A/B liver function developed grade III/IV adverse events (P = 0.7). Meta-regression analysis showed similar rates of treatment discontinuation without progression (P = 0.31) and treatment-related death (P = 0.94) in patients with CP-B liver function. CONCLUSION CP-B liver function (versus CP-A) is associated with worse OS (but the similar response rate, safety and tolerability of first-line sorafenib, is unlikely to be clinically meaningful).
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Affiliation(s)
- Mairéad Geraldine McNamara
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, UK; University of Manchester, Division of Cancer Sciences, Manchester, M20 4BX, UK.
| | - Astrid E Slagter
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, UK; University of Amsterdam, the Netherlands
| | - Christina Nuttall
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, UK
| | - Melissa Frizziero
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, UK
| | - Rille Pihlak
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, UK; University of Manchester, Division of Cancer Sciences, Manchester, M20 4BX, UK
| | - Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, UK
| | - Noor Tariq
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, UK; University of Manchester, Division of Cancer Sciences, Manchester, M20 4BX, UK
| | - Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, UK; University of Manchester, Division of Cancer Sciences, Manchester, M20 4BX, UK
| | - Richard A Hubner
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, UK
| | - Jennifer J Knox
- Department of Medical Oncology, Princess Margaret Cancer Centre/University of Toronto, 610 University Avenue, Toronto, Ontario, M5G 2M9, Canada
| | - Eitan Amir
- Department of Medical Oncology, Princess Margaret Cancer Centre/University of Toronto, 610 University Avenue, Toronto, Ontario, M5G 2M9, Canada
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Zhao P, Li M, Wang Y, Chen Y, He C, Zhang X, Yang T, Lu Y, You J, Lee RJ, Xiang G. Enhancing anti-tumor efficiency in hepatocellular carcinoma through the autophagy inhibition by miR-375/sorafenib in lipid-coated calcium carbonate nanoparticles. Acta Biomater 2018; 72:248-255. [PMID: 29555460 DOI: 10.1016/j.actbio.2018.03.022] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Revised: 02/23/2018] [Accepted: 03/07/2018] [Indexed: 12/19/2022]
Abstract
Sorafenib is a first-line drug for hepatocellular carcinoma (HCC). Autophagy has been shown to facilitate sorafenib resistance. miR-375 has been shown to be an inhibitor of autophagy. In this study, miR-375 and sorafenib were co-loaded into calcium carbonate nanoparticles with lipid coating (miR-375/Sf-LCC NPs). The nanoparticles had high loading efficiency and were ∼50 nm in diameter. Besides, the NPs could increase the stability and residence time of both drugs. Moreover, we demonstrated that autophagy was activated in HCC cells by sorafenib but not by miR-375/Sf-LCC NPs. In vitro, miR-375/Sf-LCC NPs exhibited pH-dependent drug release and potent cytotoxicity. In vivo, miR-375/Sf-LCC NPs increased miR-375 and sorafenib uptake in tumor (2 folds compared with Lipofectamine 2000-miR-375 and 2-5 folds compared with free sorafenib). Furthermore, miR-375/Sf-LCC NPs showed greatly enhanced therapeutic efficacy in an HCC xenograft model. These findings suggest that miR-375/Sf-LCC NPs may be a promising agent for the HCC therapy. STATEMENT OF SIGNIFICANCE Hepatocellular carcinoma (HCC) is the most common primary liver tumor and the third leading cause of cancer mortality globally. In this manuscript, miR-375 and sorafenib were co-loaded into calcium carbonate nanoparticles with lipid coating (miR-375/Sf-LCC NPs) to treat HCC. We demonstrated that miR-375/Sf-LCC NPs can deliver sorafenib and miR-375 into HCC cells and tumor tissues, increase drug retention time in tumor, significantly inhibit autophagy and produce enhanced anti-tumor effect.
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Montella L, Palmieri G, Addeo R, Del Prete S. Hepatocellular carcinoma: Will novel targeted drugs really impact the next future? World J Gastroenterol 2016; 22:6114-6126. [PMID: 27468204 PMCID: PMC4945973 DOI: 10.3748/wjg.v22.i27.6114] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2016] [Revised: 05/09/2016] [Accepted: 06/15/2016] [Indexed: 02/06/2023] Open
Abstract
Cancer treatment has been revolutionized by the advent of new molecular targeted and immunotherapeutic agents. Identification of the role of tumor angiogenesis changed the understanding of many tumors. After the unsuccessful results with chemotherapy, sorafenib, by interfering with angiogenic pathways, has become pivotal in the treatment of hepatocellular carcinoma. Sorafenib is the only systemic treatment to show a modest but statistically significant survival benefit. All novel drugs and strategies for treatment of advanced hepatocellular carcinoma must be compared with the results obtained with sorafenib, but no new drug or drug combination has yet achieved better results. In our opinion, the efforts to impact the natural history of the disease will be directed not only to drug development but also to understanding the underlying liver disease (usually hepatitis B virus- or hepatitis C virus-related) and to interrupting the progression of cirrhosis. It will be important to define the role and amount of mutations in the complex pathogenesis of hepatocellular carcinoma and to better integrate locoregional and systemic therapies. It will be important also to optimize the therapeutic strategies with existing chemotherapeutic drugs and new targeted agents.
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Xia F, Wu LL, Lau WY, Huan HB, Wen XD, Ma KS, Li XW, Bie P. Adjuvant sorafenib after heptectomy for Barcelona Clinic Liver Cancer-stage C hepatocellular carcinoma patients. World J Gastroenterol 2016; 22:5384-5392. [PMID: 27340354 PMCID: PMC4910659 DOI: 10.3748/wjg.v22.i23.5384] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2016] [Revised: 03/31/2016] [Accepted: 04/20/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the efficacy and safety of adjuvant sorafenib after curative resection for patients with Barcelona Clinic Liver Cancer (BCLC)-stage C hepatocellular carcinoma (HCC).
METHODS: Thirty-four HCC patients, classified as BCLC-stage C, received adjuvant sorafenib for high-risk of tumor recurrence after curative hepatectomy at a tertiary care university hospital. The study group was compared with a case-matched control group of 68 patients who received curative hepatectomy for HCC during the study period in a 1:2 ratio.
RESULTS: The tumor recurrence rate was markedly lower in the sorafenib group (15/34, 44.1%) than in the control group (51/68, 75%, P = 0.002). The median disease-free survival was 12 mo in the study group and 10 mo in the control group. Tumor number more than 3, macrovascular invasion, hilar lymph nodes metastasis, and treatment with sorafenib were significant factors of disease-free survival by univariate analysis. Tumor number more than 3 and treatment with sorafenib were significant risk factors of disease-free survival by multivariate analysis in the Cox proportional hazards model. The disease-free survival and cumulative overall survival in the study group were significantly better than in the control group (P = 0.034 and 0.016, respectively).
CONCLUSION: Our study verifies the potential benefit and safety of adjuvant sorafenib for both decreasing HCC recurrence and extending disease-free and overall survival rates for patients with BCLC-stage C HCC after curative resection.
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Heqing Y, Bin L, Xuemei Y, Linfa L. The role and mechanism of autophagy in sorafenib targeted cancer therapy. Crit Rev Oncol Hematol 2016; 100:137-40. [PMID: 26920575 DOI: 10.1016/j.critrevonc.2016.02.006] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Revised: 01/14/2016] [Accepted: 02/10/2016] [Indexed: 12/21/2022] Open
Abstract
Targeting kinase inhibitors (TKIs) are effective tools for treating advanced cancer. However, acquired resistance represents a roadblock in the use of TKIs, such as sorafenib, for cancer therapy. Understanding the acquisition of resistance to sorafenib will help doctors to cope with acquired resistance to TKIs in general and to develop personalized medicine strategies for cancer patients. Autophagy is a biological process that occurs in normal organisms. However, it is also a component of multiple disease processes, including cancer development and progression. However, the roles of autophagy in cancer and in response to cancer therapy are controversial. In this review, we summarize the progress in autophagy and sorafenib resistance research, which is representative of acquired resistance to targeted cancer therapy.
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Affiliation(s)
- Yi Heqing
- Department of Nuclear Medicine, Zhejiang Cancer Hospital, 38 Guangji Road, Hangzhou, Zhejiang Province 310021, PR China
| | - Long Bin
- Department of Nuclear Medicine, Zhejiang Cancer Hospital, 38 Guangji Road, Hangzhou, Zhejiang Province 310021, PR China
| | - Ye Xuemei
- Department of Nuclear Medicine, Zhejiang Cancer Hospital, 38 Guangji Road, Hangzhou, Zhejiang Province 310021, PR China
| | - Li Linfa
- Department of Nuclear Medicine, Zhejiang Cancer Hospital, 38 Guangji Road, Hangzhou, Zhejiang Province 310021, PR China.
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Sonntag R, Gassler N, Bangen JM, Trautwein C, Liedtke C. Pro-apoptotic Sorafenib signaling in murine hepatocytes depends on malignancy and is associated with PUMA expression in vitro and in vivo. Cell Death Dis 2014; 5:e1030. [PMID: 24481444 PMCID: PMC4040679 DOI: 10.1038/cddis.2013.557] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2013] [Revised: 12/05/2013] [Accepted: 12/13/2013] [Indexed: 12/16/2022]
Abstract
The multi-kinase inhibitor Sorafenib increases the survival of patients with advanced hepatocellular carcinoma (HCC). Current data suggest that Sorafenib inhibits cellular proliferation and angiogenesis and promotes apoptosis. However, the underlying pro-apoptotic molecular mechanisms are incompletely understood. Here we compared the pro-apoptotic and anti-proliferative properties of Sorafenib in murine hepatoma cells and syngeneic healthy hepatocytes in vitro and in animal models of HCC and liver regeneration in vivo. In vitro, we demonstrate that cell cycle activity and expression of anti-apoptotic Bcl-2 like proteins are similarly downregulated by Sorafenib in Hepa1-6 hepatoma cells and in syngeneic primary hepatocytes. However, Sorafenib-mediated activation of caspase-3 and induction of apoptosis were exclusively found in hepatoma cells, but not in matching primary hepatocytes. We validated these findings in vivo by applying an isograft HCC transplantation model and partial hepatectomy (PH) in C57BL/6 mice. Sorafenib treatment activated caspase-3 and thus apoptosis selectively in small tumor foci that originated from implanted Hepa1-6 cells but not in surrounding healthy hepatocytes. Similarly, Sorafenib did not induce apoptosis after PH. However, Sorafenib treatment transiently inhibited cell cycle progression and resulted in mitotic catastrophe and enhanced non-apoptotic liver injury during regeneration. Importantly, Sorafenib-mediated apoptosis in hepatoma cells was associated with the expression of p53-upregulated-modulator-of-apoptosis (PUMA). In contrast, regenerating livers after PH revealed downregulation of PUMA and were completely protected from Sorafenib-mediated apoptosis. We conclude that Sorafenib induces apoptosis selectively in hepatoma cells but not in healthy hepatocytes and can additionally increase non-apoptotic hepatocyte injury in the regenerating liver.
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Affiliation(s)
- R Sonntag
- Department of Medicine III, University Hospital Aachen, RWTH Aachen University, Aachen, Germany
| | - N Gassler
- Institute of Pathology, University Hospital Aachen, RWTH Aachen University, Aachen, Germany
| | - J-M Bangen
- Department of Medicine III, University Hospital Aachen, RWTH Aachen University, Aachen, Germany
| | - C Trautwein
- Department of Medicine III, University Hospital Aachen, RWTH Aachen University, Aachen, Germany
| | - C Liedtke
- Department of Medicine III, University Hospital Aachen, RWTH Aachen University, Aachen, Germany
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