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Kumar U. Somatostatin and Somatostatin Receptors in Tumour Biology. Int J Mol Sci 2023; 25:436. [PMID: 38203605 PMCID: PMC10779198 DOI: 10.3390/ijms25010436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 12/24/2023] [Accepted: 12/25/2023] [Indexed: 01/12/2024] Open
Abstract
Somatostatin (SST), a growth hormone inhibitory peptide, is expressed in endocrine and non-endocrine tissues, immune cells and the central nervous system (CNS). Post-release from secretory or immune cells, the first most appreciated role that SST exhibits is the antiproliferative effect in target tissue that served as a potential therapeutic intervention in various tumours of different origins. The SST-mediated in vivo and/or in vitro antiproliferative effect in the tumour is considered direct via activation of five different somatostatin receptor subtypes (SSTR1-5), which are well expressed in most tumours and often more than one receptor in a single cell. Second, the indirect effect is associated with the regulation of growth factors. SSTR subtypes are crucial in tumour diagnosis and prognosis. In this review, with the recent development of new SST analogues and receptor-specific agonists with emerging functional consequences of signaling pathways are promising therapeutic avenues in tumours of different origins that are discussed.
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Affiliation(s)
- Ujendra Kumar
- Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC V6T 1Z3, Canada
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Antitumoral and Anti-inflammatory Roles of Somatostatin and Its Analogs in Hepatocellular Carcinoma. Anal Cell Pathol (Amst) 2021; 2021:1840069. [PMID: 34873567 PMCID: PMC8643256 DOI: 10.1155/2021/1840069] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 11/12/2021] [Indexed: 11/22/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and affects about 8% of cirrhotic patients, with a recurrence rate of over 50%. There are numerous therapies available for the treatment of HCC, depending on cancer staging and condition of the patient. The complexity of the treatment is also justified by the unique pathogenesis of HCC that involves intricate processes such as chronic inflammation, fibrosis, and multiple molecular carcinogenesis events. During the last three decades, multiple in vivo and in vitro experiments have used somatostatin and its analogs (SSAs) to reduce the proliferative and metastatic potential of hepatoma cells by inducing their apoptosis and reducing angiogenesis and the inflammatory component of HCC. Most experiments have proven successful, revealing several different pathways and mechanisms corresponding to the aforementioned functions. Moreover, a correlation between specific effects and expression of somatostatin receptors (SSTRs) was observed in the studied cells. Clinical trials have tested either somatostatin or an analog, alone or in combination with other drugs, to explore the potential effects on HCC patients, in various stages of the disease. While the majority of these clinical trials exhibited minor to moderate success, some other studies were inconclusive or even reported negative outcomes. A complete evaluation of the efficacy of somatostatin and SSAs is still the matter of intense debate, and, if deemed useful, these substances may play a beneficial role in the management of HCC patients.
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Brown ZJ, Hewitt DB, Pawlik TM. Combination therapies plus transarterial chemoembolization in hepatocellular carcinoma: a snapshot of clinical trial progress. Expert Opin Investig Drugs 2021; 31:379-391. [PMID: 34788184 DOI: 10.1080/13543784.2022.2008355] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Unfortunately, some hepatocellular carcinoma (HCC) patients do not qualify for curative-intent treatments such as surgical resection or transplantation. Hence, locoregional treatments such as transarterial chemoembolization (TACE) remain instrumental in the treatment of HCC. Systemic therapy has improved over the past decade with the introduction of combination atezolizumab and bevacizumab as the new standard of care for advanced disease. These new therapies are currently under investigation in combination with TACE. AREA COVERED Combination therapies with TACE including systemic therapies, locoregional therapies, and immunotherapies are reviewed. EXPERT OPINION There has been limited progress in the management of advanced and intermediate HCC. Recent advances in the management of advanced disease with systemic therapy could be beneficial in combination with TACE for the treatment of intermediate stage disease. Immune based therapies are potentially beneficial in combination with TACE because TACE may produce increased antigen release and immune recognition.
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Affiliation(s)
- Zachary J Brown
- Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - D Brock Hewitt
- Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Timothy M Pawlik
- Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA
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Eychenne R, Bouvry C, Bourgeois M, Loyer P, Benoist E, Lepareur N. Overview of Radiolabeled Somatostatin Analogs for Cancer Imaging and Therapy. Molecules 2020; 25:4012. [PMID: 32887456 PMCID: PMC7504749 DOI: 10.3390/molecules25174012] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 08/28/2020] [Accepted: 09/01/2020] [Indexed: 12/19/2022] Open
Abstract
Identified in 1973, somatostatin (SST) is a cyclic hormone peptide with a short biological half-life. Somatostatin receptors (SSTRs) are widely expressed in the whole body, with five subtypes described. The interaction between SST and its receptors leads to the internalization of the ligand-receptor complex and triggers different cellular signaling pathways. Interestingly, the expression of SSTRs is significantly enhanced in many solid tumors, especially gastro-entero-pancreatic neuroendocrine tumors (GEP-NET). Thus, somatostatin analogs (SSAs) have been developed to improve the stability of the endogenous ligand and so extend its half-life. Radiolabeled analogs have been developed with several radioelements such as indium-111, technetium-99 m, and recently gallium-68, fluorine-18, and copper-64, to visualize the distribution of receptor overexpression in tumors. Internal metabolic radiotherapy is also used as a therapeutic strategy (e.g., using yttrium-90, lutetium-177, and actinium-225). With some radiopharmaceuticals now used in clinical practice, somatostatin analogs developed for imaging and therapy are an example of the concept of personalized medicine with a theranostic approach. Here, we review the development of these analogs, from the well-established and authorized ones to the most recently developed radiotracers, which have better pharmacokinetic properties and demonstrate increased efficacy and safety, as well as the search for new clinical indications.
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Affiliation(s)
- Romain Eychenne
- UPS, CNRS, SPCMIB (Laboratoire de Synthèse et Physico-Chimie de Molécules d’Intérêt Biologique)—UMR 5068, Université de Toulouse, F-31062 Toulouse, France; (R.E.); (E.B.)
- Groupement d’Intérêt Public ARRONAX, 1 Rue Aronnax, F-44817 Saint Herblain, France;
- CNRS, CRCINA (Centre de Recherche en Cancérologie et Immunologie Nantes—Angers)—UMR 1232, ERL 6001, Inserm, Université de Nantes, F-44000 Nantes, France
| | - Christelle Bouvry
- Comprehensive Cancer Center Eugène Marquis, Rennes, F-35000, France;
- CNRS, ISCR (Institut des Sciences Chimiques de Rennes)—UMR 6226, Univ Rennes, F-35000 Rennes, France
| | - Mickael Bourgeois
- Groupement d’Intérêt Public ARRONAX, 1 Rue Aronnax, F-44817 Saint Herblain, France;
- CNRS, CRCINA (Centre de Recherche en Cancérologie et Immunologie Nantes—Angers)—UMR 1232, ERL 6001, Inserm, Université de Nantes, F-44000 Nantes, France
| | - Pascal Loyer
- INRAE, Institut NUMECAN (Nutrition, Métabolismes et Cancer)—UMR_A 1341, UMR_S 1241, Inserm, Univ Rennes, F-35000 Rennes, France;
| | - Eric Benoist
- UPS, CNRS, SPCMIB (Laboratoire de Synthèse et Physico-Chimie de Molécules d’Intérêt Biologique)—UMR 5068, Université de Toulouse, F-31062 Toulouse, France; (R.E.); (E.B.)
| | - Nicolas Lepareur
- Comprehensive Cancer Center Eugène Marquis, Rennes, F-35000, France;
- INRAE, Institut NUMECAN (Nutrition, Métabolismes et Cancer)—UMR_A 1341, UMR_S 1241, Inserm, Univ Rennes, F-35000 Rennes, France;
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Reynaert H, Colle I. Treatment of Advanced Hepatocellular Carcinoma with Somatostatin Analogues: A Review of the Literature. Int J Mol Sci 2019; 20:ijms20194811. [PMID: 31569719 PMCID: PMC6801667 DOI: 10.3390/ijms20194811] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 09/20/2019] [Accepted: 09/25/2019] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma, one of the most dreaded complications of cirrhosis, is a frequent cancer with high mortality. Early primary liver cancer can be treated by surgery or ablation techniques, but advanced hepatocellular carcinoma remains a challenge for clinicians. Most of these patients have underlying cirrhosis, which complicates or even precludes treatment. Therefore, efficacious treatments without major side effects are welcomed. Initial results of treatment of advanced hepatocellular carcinoma with somatostatin analogues were promising, but subsequent trials have resulted in conflicting outcomes. This might be explained by different patient populations, differences in dosage and type of treatment and differences in somatostatin receptor expression in the tumor or surrounding tissue. It has been shown that the expression of somatostatin receptors in the tumor might be of importance to select patients who could benefit from treatment with somatostatin analogues. Moreover, somatostatin receptor expression in hepatocellular carcinoma has been shown to correlate with recurrence, prognosis, and survival. In this review, we will summarize the available data on treatment of primary liver cancer with somatostatin analogues and analyze the current knowledge of somatostatin receptor expression in hepatocellular carcinoma and its possible clinical impact.
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Affiliation(s)
- Hendrik Reynaert
- Department of Gastroenterology-hepatology UZBrussel, Laarbeeklaan 101, 1090 Brussels, Belgium.
- Liver Cell Biology Lab, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium.
| | - Isabelle Colle
- Department of Gastroenterology-hepatology, ASZ Aalst, Merestraat 80, 9300 Aalst, Belgium.
- Department of Gastroenterology-hepatology, Ghent University, De Pintelaan, 9000 Ghent, Belgium.
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Nanomedicine as a putative approach for active targeting of hepatocellular carcinoma. Semin Cancer Biol 2019; 69:91-99. [PMID: 31421265 DOI: 10.1016/j.semcancer.2019.08.016] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2019] [Revised: 08/04/2019] [Accepted: 08/13/2019] [Indexed: 12/12/2022]
Abstract
The effectiveness of chemotherapy in hepatocellular carcinoma (HCC) is restricted by chemo-resistance and systemic side effects. To improve the efficacy and safety of chemotherapeutics in HCC management, scientists have attempted to deliver these drugs to malignant tissues using targeted carriers as nanoparticles (NPs). Among the three types of NPs targeting (active, passive, and stimuli-responsive), active targeting is the most commonly investigated in HCC treatment. Despite the observed promising results so far, clinical research on nanomedicine targeting for HCC treatment still faces many challenges.These include batch-to-batch physicochemical properties' variations, limiting large scale production and insufficient data on human and environmental toxicities. This review summarized the characteristics of different nanocarriers, ligands, targeted receptors on HCC cells and provided recommendations to overcome the challenges, facing this novel line of treatment for HCC.
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Zhou RS, Wang XW, Sun QF, Ye ZJ, Liu JW, Zhou DH, Tang Y. Anticancer Effects of Emodin on HepG2 Cell: Evidence from Bioinformatic Analysis. BIOMED RESEARCH INTERNATIONAL 2019; 2019:3065818. [PMID: 31236404 PMCID: PMC6545785 DOI: 10.1155/2019/3065818] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Revised: 03/31/2019] [Accepted: 04/23/2019] [Indexed: 01/18/2023]
Abstract
Hepatocellular carcinoma (HCC) is a primary cause of cancer-related death in the world. Despite the fact that there are many methods to treat HCC, the 5-year survival rate of HCC is still at a low level. Emodin can inhibit the growth of HCC cells in vitro and in vivo. However, the gene regulation of emodin in HCC has not been well studied. In our research, RNA sequencing technology was used to identify the differentially expressed genes (DEGs) in HepG2 cells induced by emodin. A total of 859 DEGs were identified, including 712 downregulated genes and 147 upregulated genes in HepG2 cells treated with emodin. We used DAVID for function and pathway enrichment analysis. The protein-protein interaction (PPI) network was constructed using STRING, and Cytoscape was used for module analysis. The enriched functions and pathways of the DEGs include positive regulation of apoptotic process, structural molecule activity and lipopolysaccharide binding, protein digestion and absorption, ECM-receptor interaction, complement and coagulation cascades, and MAPK signaling pathway. 25 hub genes were identified and pathway analysis revealed that these genes were mainly enriched in neuropeptide signaling pathway, inflammatory response, and positive regulation of cytosolic calcium ion concentration. Survival analysis showed that LPAR6, C5, SSTR5, GPR68, and P2RY4 may be involved in the molecular mechanisms of emodin therapy for HCC. A quantitative real-time PCR (qRT-PCR) assay showed that the mRNA levels of LPAR6, C5, SSTR5, GPR68, and P2RY4 were significantly decreased in HepG2 cells treated with emodin. In conclusion, the identified DEGs and hub genes in the present study provide new clues for further researches on the molecular mechanisms of emodin.
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Affiliation(s)
- Rui-sheng Zhou
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiong-Wen Wang
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Qin-feng Sun
- Stomatological Hospital of Shandong University, Shandong, China
| | - Zeng Jie Ye
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | | | - Dai-Han Zhou
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ying Tang
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
- Guangzhou University of Chinese Medicine, Guangzhou, China
- Lingnan Medical Research Center of Guangzhou University of Chinese Medicine, Guangzhou, China
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Varshosaz J, Raghami F, Rostami M, Jahanian A. PEGylated trimethylchitosan emulsomes conjugated to octreotide for targeted delivery of sorafenib to hepatocellular carcinoma cells of HepG2. J Liposome Res 2019; 29:383-398. [PMID: 30668221 DOI: 10.1080/08982104.2019.1570250] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The current study aimed to develop PEGylated trimethyl chitosan (TMC) coated emulsomes (EMs) conjugated with octreotide for targeted delivery of sorafenib to hepatocellular carcinoma cells (HCC) of HepG2. Sorafenib loaded TMC coated EMs were prepared by the emulsion evaporation method and characterized concerning particle size, zeta potential, drug encapsulation efficiency, and in vitro drug release. Synthesized EMs were then conjugated to octreotide. The cytotoxicity of the targeted and non-targeted EMs was determined by cellular uptake and MTT assay on HepG2 cell. Cell cycle assay was also studied using flow cytometry. The results showed the optimized EMs had the particle size of 127 nm, zeta potential of -5.41 mV, loading efficiency of 95%, and drug release efficiency of 62% within 52 h. Octreotide was attached efficiently to the surface of EMs as much as 71%. MTT assay and cellular uptake studies showed that targeted EMs had more cytotoxicity than free sorafenib and non-targeted EMs. Cell cycle analyses revealed that there was a significant more accumulation of targeted EMs treated HepG2 cells in the G1 phase than free sorafenib and non-targeted EMs. The results indicate that designed EMs may be promising for the treatment of hepatocellular carcinoma.
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Affiliation(s)
- Jaleh Varshosaz
- Department of Pharmaceutics, School of Pharmacy and Novel Drug Delivery Systems Research Centre, Isfahan University of Medical Sciences , Isfahan , Iran
| | - Fatemeh Raghami
- Department of Pharmaceutics, School of Pharmacy and Novel Drug Delivery Systems Research Centre, Isfahan University of Medical Sciences , Isfahan , Iran
| | - Mahboubeh Rostami
- Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences , Isfahan , Iran
| | - Ali Jahanian
- Department of Pharmaceutical Biotechnology, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences , Isfahan , Iran
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Günther T, Tulipano G, Dournaud P, Bousquet C, Csaba Z, Kreienkamp HJ, Lupp A, Korbonits M, Castaño JP, Wester HJ, Culler M, Melmed S, Schulz S. International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature. Pharmacol Rev 2018; 70:763-835. [PMID: 30232095 PMCID: PMC6148080 DOI: 10.1124/pr.117.015388] [Citation(s) in RCA: 165] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Somatostatin, also known as somatotropin-release inhibitory factor, is a cyclopeptide that exerts potent inhibitory actions on hormone secretion and neuronal excitability. Its physiologic functions are mediated by five G protein-coupled receptors (GPCRs) called somatostatin receptor (SST)1-5. These five receptors share common structural features and signaling mechanisms but differ in their cellular and subcellular localization and mode of regulation. SST2 and SST5 receptors have evolved as primary targets for pharmacological treatment of pituitary adenomas and neuroendocrine tumors. In addition, SST2 is a prototypical GPCR for the development of peptide-based radiopharmaceuticals for diagnostic and therapeutic interventions. This review article summarizes findings published in the last 25 years on the physiology, pharmacology, and clinical applications related to SSTs. We also discuss potential future developments and propose a new nomenclature.
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Affiliation(s)
- Thomas Günther
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany (T.G., A.L., S.S.); Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (G.T.); PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France (P.D., Z.C.); Cancer Research Center of Toulouse, INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France (C.B.); Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.-J.K.); Centre for Endocrinology, William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, United Kingdom (M.K.); Maimonides Institute for Biomedical Research of Cordoba, Córdoba, Spain (J.P.C.); Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain (J.P.C.); Reina Sofia University Hospital, Córdoba, Spain (J.P.C.); CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain (J.P.C.); Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany (H.-J.W.); Culler Consulting LLC, Hopkinton, Massachusetts (M.C.); and Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California (S.M.)
| | - Giovanni Tulipano
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany (T.G., A.L., S.S.); Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (G.T.); PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France (P.D., Z.C.); Cancer Research Center of Toulouse, INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France (C.B.); Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.-J.K.); Centre for Endocrinology, William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, United Kingdom (M.K.); Maimonides Institute for Biomedical Research of Cordoba, Córdoba, Spain (J.P.C.); Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain (J.P.C.); Reina Sofia University Hospital, Córdoba, Spain (J.P.C.); CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain (J.P.C.); Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany (H.-J.W.); Culler Consulting LLC, Hopkinton, Massachusetts (M.C.); and Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California (S.M.)
| | - Pascal Dournaud
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany (T.G., A.L., S.S.); Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (G.T.); PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France (P.D., Z.C.); Cancer Research Center of Toulouse, INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France (C.B.); Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.-J.K.); Centre for Endocrinology, William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, United Kingdom (M.K.); Maimonides Institute for Biomedical Research of Cordoba, Córdoba, Spain (J.P.C.); Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain (J.P.C.); Reina Sofia University Hospital, Córdoba, Spain (J.P.C.); CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain (J.P.C.); Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany (H.-J.W.); Culler Consulting LLC, Hopkinton, Massachusetts (M.C.); and Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California (S.M.)
| | - Corinne Bousquet
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany (T.G., A.L., S.S.); Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (G.T.); PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France (P.D., Z.C.); Cancer Research Center of Toulouse, INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France (C.B.); Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.-J.K.); Centre for Endocrinology, William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, United Kingdom (M.K.); Maimonides Institute for Biomedical Research of Cordoba, Córdoba, Spain (J.P.C.); Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain (J.P.C.); Reina Sofia University Hospital, Córdoba, Spain (J.P.C.); CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain (J.P.C.); Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany (H.-J.W.); Culler Consulting LLC, Hopkinton, Massachusetts (M.C.); and Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California (S.M.)
| | - Zsolt Csaba
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany (T.G., A.L., S.S.); Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (G.T.); PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France (P.D., Z.C.); Cancer Research Center of Toulouse, INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France (C.B.); Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.-J.K.); Centre for Endocrinology, William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, United Kingdom (M.K.); Maimonides Institute for Biomedical Research of Cordoba, Córdoba, Spain (J.P.C.); Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain (J.P.C.); Reina Sofia University Hospital, Córdoba, Spain (J.P.C.); CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain (J.P.C.); Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany (H.-J.W.); Culler Consulting LLC, Hopkinton, Massachusetts (M.C.); and Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California (S.M.)
| | - Hans-Jürgen Kreienkamp
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany (T.G., A.L., S.S.); Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (G.T.); PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France (P.D., Z.C.); Cancer Research Center of Toulouse, INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France (C.B.); Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.-J.K.); Centre for Endocrinology, William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, United Kingdom (M.K.); Maimonides Institute for Biomedical Research of Cordoba, Córdoba, Spain (J.P.C.); Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain (J.P.C.); Reina Sofia University Hospital, Córdoba, Spain (J.P.C.); CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain (J.P.C.); Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany (H.-J.W.); Culler Consulting LLC, Hopkinton, Massachusetts (M.C.); and Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California (S.M.)
| | - Amelie Lupp
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany (T.G., A.L., S.S.); Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (G.T.); PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France (P.D., Z.C.); Cancer Research Center of Toulouse, INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France (C.B.); Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.-J.K.); Centre for Endocrinology, William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, United Kingdom (M.K.); Maimonides Institute for Biomedical Research of Cordoba, Córdoba, Spain (J.P.C.); Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain (J.P.C.); Reina Sofia University Hospital, Córdoba, Spain (J.P.C.); CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain (J.P.C.); Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany (H.-J.W.); Culler Consulting LLC, Hopkinton, Massachusetts (M.C.); and Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California (S.M.)
| | - Márta Korbonits
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany (T.G., A.L., S.S.); Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (G.T.); PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France (P.D., Z.C.); Cancer Research Center of Toulouse, INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France (C.B.); Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.-J.K.); Centre for Endocrinology, William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, United Kingdom (M.K.); Maimonides Institute for Biomedical Research of Cordoba, Córdoba, Spain (J.P.C.); Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain (J.P.C.); Reina Sofia University Hospital, Córdoba, Spain (J.P.C.); CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain (J.P.C.); Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany (H.-J.W.); Culler Consulting LLC, Hopkinton, Massachusetts (M.C.); and Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California (S.M.)
| | - Justo P Castaño
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany (T.G., A.L., S.S.); Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (G.T.); PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France (P.D., Z.C.); Cancer Research Center of Toulouse, INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France (C.B.); Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.-J.K.); Centre for Endocrinology, William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, United Kingdom (M.K.); Maimonides Institute for Biomedical Research of Cordoba, Córdoba, Spain (J.P.C.); Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain (J.P.C.); Reina Sofia University Hospital, Córdoba, Spain (J.P.C.); CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain (J.P.C.); Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany (H.-J.W.); Culler Consulting LLC, Hopkinton, Massachusetts (M.C.); and Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California (S.M.)
| | - Hans-Jürgen Wester
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany (T.G., A.L., S.S.); Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (G.T.); PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France (P.D., Z.C.); Cancer Research Center of Toulouse, INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France (C.B.); Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.-J.K.); Centre for Endocrinology, William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, United Kingdom (M.K.); Maimonides Institute for Biomedical Research of Cordoba, Córdoba, Spain (J.P.C.); Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain (J.P.C.); Reina Sofia University Hospital, Córdoba, Spain (J.P.C.); CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain (J.P.C.); Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany (H.-J.W.); Culler Consulting LLC, Hopkinton, Massachusetts (M.C.); and Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California (S.M.)
| | - Michael Culler
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany (T.G., A.L., S.S.); Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (G.T.); PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France (P.D., Z.C.); Cancer Research Center of Toulouse, INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France (C.B.); Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.-J.K.); Centre for Endocrinology, William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, United Kingdom (M.K.); Maimonides Institute for Biomedical Research of Cordoba, Córdoba, Spain (J.P.C.); Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain (J.P.C.); Reina Sofia University Hospital, Córdoba, Spain (J.P.C.); CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain (J.P.C.); Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany (H.-J.W.); Culler Consulting LLC, Hopkinton, Massachusetts (M.C.); and Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California (S.M.)
| | - Shlomo Melmed
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany (T.G., A.L., S.S.); Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (G.T.); PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France (P.D., Z.C.); Cancer Research Center of Toulouse, INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France (C.B.); Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.-J.K.); Centre for Endocrinology, William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, United Kingdom (M.K.); Maimonides Institute for Biomedical Research of Cordoba, Córdoba, Spain (J.P.C.); Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain (J.P.C.); Reina Sofia University Hospital, Córdoba, Spain (J.P.C.); CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain (J.P.C.); Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany (H.-J.W.); Culler Consulting LLC, Hopkinton, Massachusetts (M.C.); and Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California (S.M.)
| | - Stefan Schulz
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich-Schiller-University, Jena, Germany (T.G., A.L., S.S.); Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy (G.T.); PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France (P.D., Z.C.); Cancer Research Center of Toulouse, INSERM UMR 1037-University Toulouse III Paul Sabatier, Toulouse, France (C.B.); Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (H.-J.K.); Centre for Endocrinology, William Harvey Research Institute, Barts and London School of Medicine, Queen Mary University of London, London, United Kingdom (M.K.); Maimonides Institute for Biomedical Research of Cordoba, Córdoba, Spain (J.P.C.); Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, Spain (J.P.C.); Reina Sofia University Hospital, Córdoba, Spain (J.P.C.); CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain (J.P.C.); Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany (H.-J.W.); Culler Consulting LLC, Hopkinton, Massachusetts (M.C.); and Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California (S.M.)
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11
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Lohitesh K, Chowdhury R, Mukherjee S. Resistance a major hindrance to chemotherapy in hepatocellular carcinoma: an insight. Cancer Cell Int 2018; 18:44. [PMID: 29568237 PMCID: PMC5859782 DOI: 10.1186/s12935-018-0538-7] [Citation(s) in RCA: 184] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Accepted: 03/12/2018] [Indexed: 12/18/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer mortality, accounting for almost 90% of total liver cancer burden. Surgical resection followed by adjuvant and systemic chemotherapy are the most meticulously followed treatment procedures but the complex etiology and high metastatic potential of the disease renders surgical treatment futile in majority of the cases. Another hindrance to the scenario is the acquired resistance to drugs resulting in relapse of the disease. Hence, to provide insights into development of novel therapeutic targets and diagnostic biomarkers, this review focuses on the various molecular mechanisms underlying chemoresistance in HCC. We have provided a comprehensive summary of the various strategies adopted by HCC cells, extending from apoptosis evasion, autophagy activation, drug expulsion to epigenetic transformation as modes of therapy resistance. The role of stem cells in imparting chemoresistance is also discussed. Furthermore, the review also focuses on how this knowledge might be exploited for the development of an effective, prospective therapy against HCC.
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Affiliation(s)
- K Lohitesh
- Department of Biological-Sciences, Birla Institute of Technology and Sciences (BITS), Campus, VidyaVihar, Pilani, Rajasthan 333031 India
| | - Rajdeep Chowdhury
- Department of Biological-Sciences, Birla Institute of Technology and Sciences (BITS), Campus, VidyaVihar, Pilani, Rajasthan 333031 India
| | - Sudeshna Mukherjee
- Department of Biological-Sciences, Birla Institute of Technology and Sciences (BITS), Campus, VidyaVihar, Pilani, Rajasthan 333031 India
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12
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Feun LG, Wangpaichitr M, Li YY, Kwon D, Richman SP, Hosein PJ, Savaraj N. Phase II trial of SOM230 (pasireotide LAR) in patients with unresectable hepatocellular carcinoma. J Hepatocell Carcinoma 2018; 5:9-15. [PMID: 29392123 PMCID: PMC5769585 DOI: 10.2147/jhc.s153672] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Background A phase II trial of pasireotide was performed to assess its efficacy and safety in advanced or metastatic hepatocellular carcinoma (HCC). Patients and methods Patients with advanced HCC and Child-Pugh score ≤7 received pasireotide LAR 60 mg intramuscularly every 28 days. Primary endpoint was disease control rate. Secondary endpoints were time to tumor progression, response rate, treatment-related adverse events, and overall survival. Serum insulin growth factor-1 was measured before and after pasireotide. Results Twenty patients were treated and evaluable. Eighteen patients (90%) had prior therapy; 16 patients (80%) had multiple therapies. Median age was 65, 75% had Barcelona Clinic Liver Cancer stage C, and 55% had metastatic disease. The main toxicity was hyperglycemia. Rare adverse effects included reversible grade 4 elevation in alanina transaminase/aspartate transaminase in one patient. The best response was stable disease in 9 patients (45%). Median time to tumor progression for the 20 patients was 3 months, and median survival was 9 months. Conclusion Pasireotide had limited clinical benefit as second-line or third-line treatment in patients with advanced or metastatic HCC. Low baseline insulin growth factor-1 level may be indicative when SOM230 treatment may be ineffective, and decreasing levels after treatment may be indicative of disease control.
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Affiliation(s)
- Lynn G Feun
- Department of Medicine, Medical Oncology, Sylvester Comprehensive Cancer Center, University of Miami
| | | | - Ying-Ying Li
- Department of Medicine, Medical Oncology, Sylvester Comprehensive Cancer Center, University of Miami
| | - Deukwoo Kwon
- Biostatistics and Bioinformatics Core, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA
| | - Stephen P Richman
- Department of Medicine, Medical Oncology, Sylvester Comprehensive Cancer Center, University of Miami
| | - Peter J Hosein
- Department of Medicine, Medical Oncology, Sylvester Comprehensive Cancer Center, University of Miami
| | - Niramol Savaraj
- Department of Medicine, Medical Oncology, Sylvester Comprehensive Cancer Center, University of Miami.,Department of Surgery, Miami VA Healthcare System, Research Service
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13
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Kaemmerer D, Schindler R, Mußbach F, Dahmen U, Altendorf-Hofmann A, Dirsch O, Sänger J, Schulz S, Lupp A. Somatostatin and CXCR4 chemokine receptor expression in hepatocellular and cholangiocellular carcinomas: tumor capillaries as promising targets. BMC Cancer 2017; 17:896. [PMID: 29282035 PMCID: PMC5745780 DOI: 10.1186/s12885-017-3911-3] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Accepted: 12/13/2017] [Indexed: 12/15/2022] Open
Abstract
Background Hepatocellular (HCC) and cholangiocellular carcinomas (CCC) display an exceptionally poor prognosis. Especially for advanced disease no efficient standard therapy is currently available. Recently, somatostatin analogs have been evaluated for the treatment of HCC, however, with contradictory results. Besides, for both malignancies the chemokine receptor CXCR4 has been discussed as a possible new target structure. Methods Expression of somatostatin receptor (SSTR) subtypes 1, 2A, 3, 4, and 5, and of CXCR4 was evaluated in a total of 71 HCCs and 27 CCCs by immunohistochemistry using well-characterized novel monoclonal antibodies. Results In HCC tumor cells, frequency and intensity of expression of SSTRs and CXCR4 were only low. CXCR4 was present in about 40% of the HCCs, although at a low intensity. SSTR5, SSTR2, and SSTR3 were detected in about 15%, 8%, and 5% of the HCC tumors, respectively. SSTR and CXCR4 expression was much higher in CCC than in HCC. CXCR4 and SSTR1 were present in 60% and 67% of the CCC samples, respectively, followed by SSTR2 and SSTR5, which were detected in 30% and 11% of the tumors, respectively. Most notably, CXCR4 was intensely expressed on the tumor capillaries in about 50% of the HCCs and CCCs. CXCR4 expression on tumor vessels was associated with poor patient outcomes. Conclusions CCC, but not HCC, may be suitable for SSTR-based treatments. Because of the predominant expression of SSTR1, pan-somatostatin analogs should be preferred. In both HCC and CCC, indirect targeting of tumors via the CXCR4-positive tumor capillaries may represent a promising additional therapeutic strategy. Electronic supplementary material The online version of this article (10.1186/s12885-017-3911-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Daniel Kaemmerer
- Department of General and Visceral Surgery, Zentralklinik Bad Berka, Bad Berka, Germany
| | - Robin Schindler
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Drackendorfer Str. 1, D-07747, Jena, Germany
| | - Franziska Mußbach
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, Jena, Germany
| | - Uta Dahmen
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, Jena, Germany
| | | | - Olaf Dirsch
- Institute of Pathology, Jena University Hospital, Jena, Germany
| | - Jörg Sänger
- Institute of Pathology and Cytology Bad Berka, Bad Berka, Germany
| | - Stefan Schulz
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Drackendorfer Str. 1, D-07747, Jena, Germany
| | - Amelie Lupp
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Drackendorfer Str. 1, D-07747, Jena, Germany.
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14
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Tong H, Wei B, Chen S, Xie YM, Zhang MG, Zhang LH, Huang ZY, Tang CW. Adjuvant celecoxib and lanreotide following transarterial chemoembolisation for unresectable hepatocellular carcinoma: a randomized pilot study. Oncotarget 2017; 8:48303-48312. [PMID: 28430638 PMCID: PMC5564648 DOI: 10.18632/oncotarget.15684] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Accepted: 02/15/2017] [Indexed: 02/05/2023] Open
Abstract
Recurrence of hepatocellular carcinoma (HCC) after transarterial chemoembolisation (TACE) is common due to neoangiogenesis. Cyclooxygenase-2 inhibitors and somatostatin analogues were reported to inhibit tumour angiogenesis. The pilot randomized controlled trial was aimed to prospectively evaluate the protocol of TACE combined with celecoxib and lanreotide (TACE+C+L) in patients with unresectable and advanced HCC. A total of 71 patients with HCC were enrolled and randomly assigned to either TACE (n=35) or TACE+C+L (n=36) group. Overall survival, disease control rate (DCR), and adverse events were assessed during a 3-year follow-up period. The median overall survival of the TACE+C+L group (15.0 months) was doubled compared to that of TACE group (7.5 months), p = 0.012. DCR of the TACE+C+L group was significantly higher than that of the TACE group either at 6 months (72.2% vs 42.9%, p = 0.012) or at 12 months (61.1% vs 28.6%, p = 0.006). The median overall survivals (13 months vs 4.5 months, p = 0.013) and DCR at 12 months (50% vs 13.6%, p = 0.008) of patients with advanced HCC in TACE+C+L groups were significantly higher than those in TACE group. No significant difference of adverse events was observed between the two groups. The occurrence of post-embolisation syndrome in TACE+C+L group was significantly lower than that in TACE group (16.7% vs 60.0%, p = 0.001). In conclusion, the regimen of TACE+C+L prolonged overall survival, enhanced tumour response, reduced post-embolisation syndrome and was well-tolerable in the patients with unresectable HCC. It may be more beneficial for advanced HCC.
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Affiliation(s)
- Huan Tong
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Bo Wei
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Shuang Chen
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Yong-Mei Xie
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Ming-Guang Zhang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Lin-Hao Zhang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Zhi-Yin Huang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Cheng-Wei Tang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
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15
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Klungboonkrong V, Das D, McLennan G. Molecular Mechanisms and Targets of Therapy for Hepatocellular Carcinoma. J Vasc Interv Radiol 2017; 28:949-955. [PMID: 28416267 DOI: 10.1016/j.jvir.2017.03.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Revised: 03/01/2017] [Accepted: 03/01/2017] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. HCC develops through a multistep process that involves the local tumor microenvironment, intracellular signaling pathways, and altered metabolic system that allows the cancer proliferation. Understanding the mechanisms of tumor development and progression is critical to developing improved therapies aimed at better survival. This article reviews the molecular mechanisms of HCC development and highlights the potential therapeutic targets for treatments.
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Affiliation(s)
- Vivian Klungboonkrong
- Department of Interventional Radiology, Imaging Institute, Cleveland, OH 44195; Department of Radiology, KhonKaen University, KhonKaen, Thailand
| | - Dola Das
- Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195
| | - Gordon McLennan
- Department of Interventional Radiology, Imaging Institute, Cleveland, OH 44195.
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Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer with poor prognosis. The incidence of HCC and HCC-related deaths have increased over the last several decades. However, the treatment options for advanced HCC are very limited. Sorafenib remains the only drug approved for systemic treatment for advanced HCC. However, prior to sorafenib era conventional cytotoxic chemotherapies have been studied in advanced HCC. In this review, clinical studies of systemic chemotherapy for advanced HCC will be summarized and discussed.
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Affiliation(s)
- Dae Won Kim
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Chetasi Talati
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Richard Kim
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA
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17
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Lequoy M, Desbois-Mouthon C, Wendum D, Gupta V, Blachon JL, Scatton O, Dumont S, Bonnemaire M, Schmidlin F, Rosmorduc O, Fartoux L. Somatostatin receptors in resected hepatocellular carcinoma: status and correlation with markers of poor prognosis. Histopathology 2017; 70:492-498. [PMID: 27391928 DOI: 10.1111/his.13034] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Accepted: 07/06/2016] [Indexed: 01/04/2025]
Abstract
AIMS To investigate the status of somatostatin receptors (SSTRs) in resected hepatocellular carcinoma (HCC). METHODS AND RESULTS Transcript and protein levels of SSTR2, SSTR3 and SSTR5 were investigated, with real-time polymerase chain reaction (PCR) and manual and automated immunohistochemistry (IHC), in 53 resected HCCs and paired non-tumour tissues. SSTR1, SSTR4, SSTR5TMD4 and SSTR5TMD5 were analysed with real-time PCR. SSTR3 and SSTR5 transcripts were expressed in ~25% of HCCs, but not in adjacent non-tumour tissues. SSTR1 and SSTR2 transcripts were overexpressed in 42% and 32% of HCCs, respectively. SSTR4, SSTR5TMD4 and SSTR5TMD5 were not detected. Membrane staining for SSTR2 was detected in 38% of HCCs, whereas SSTR5 protein was detectable in only 11% of HCCs. SSTR3 protein was detected in the majority of HCCs and adjacent non-tumour liver tissues, but membrane staining was <20% of that in HCCs. The results obtained with the two IHC methods were highly correlated (P < 0.0001). Statistical analyses also showed a positive correlation between SSTR2 membrane staining and cytokeratin 19 expression (P = 0.04), serum α-fetoprotein level (P = 0.002), and poor differentiation (P = 0.05). CONCLUSIONS Membrane SSTR2 is detected reliably in HCCs by IHC, and is a potential therapeutic target, as it is coexpressed with markers of poor prognosis.
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Affiliation(s)
- Marie Lequoy
- Department of Hepatology, AP-HP, Saint-Antoine Hospital, Paris, France
- Saint-Antoine Research Centre, Sorbonne Universités, UPMC Univ. Paris 06, UMR_S 938, Paris, France
| | | | - Dominique Wendum
- Saint-Antoine Research Centre, Sorbonne Universités, UPMC Univ. Paris 06, UMR_S 938, Paris, France
- Department of Pathology, AP-HP, Saint-Antoine Hospital, Paris, France
| | - Vandana Gupta
- Oncology and Biomarkers, Ipsen Biosci. Inc., Cambridge, MA, USA
| | | | - Olivier Scatton
- Saint-Antoine Research Centre, Sorbonne Universités, UPMC Univ. Paris 06, UMR_S 938, Paris, France
- Department of Hepatobiliary Surgery, AP-HP, Pitié Salpêtrière Hospital, Paris, France
| | - Sylvie Dumont
- Saint-Antoine Research Centre, Sorbonne Universités, UPMC Univ. Paris 06, UMR_S 938, Paris, France
- Department of Pathology, AP-HP, Saint-Antoine Hospital, Paris, France
| | | | | | - Olivier Rosmorduc
- Saint-Antoine Research Centre, Sorbonne Universités, UPMC Univ. Paris 06, UMR_S 938, Paris, France
- Department of Hepatology, AP-HP, Pitié Salpêtrière Hospital, Paris, France
| | - Laetitia Fartoux
- Saint-Antoine Research Centre, Sorbonne Universités, UPMC Univ. Paris 06, UMR_S 938, Paris, France
- Department of Hepatology, AP-HP, Pitié Salpêtrière Hospital, Paris, France
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18
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Lamarca A, Mendiola M, Barriuso J. Hepatocellular carcinoma: Exploring the impact of ethnicity on molecular biology. Crit Rev Oncol Hematol 2016; 105:65-72. [PMID: 27372199 DOI: 10.1016/j.critrevonc.2016.06.007] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2015] [Revised: 03/15/2016] [Accepted: 06/14/2016] [Indexed: 01/17/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common cancer in the world and the third leading cause of cancer-related death. The high rate of diagnosis in non-curable stages and the lack of novel active treatments make it necessary to review all the possible sources of misleading results in this scenario. The incidence of HCC shows clear geographical variation with higher annual incidence in Asia and Africa than in Western countries; we aimed to review the literature to find if there are different trends in the main activated molecular pathways. Hyperactivation of RAS/RAF/MEK/ERK and PI3K/AKT/mTOR signalling and epithelial to mesenchymal transition (EMT) process are more prevalent in the Western population; however, fibroblast growth factor (FGF), transforming growth factor β (TGFβ) and Notch pathways seems to be more relevant in Asian population. Whether these variations just reflect the distinct distribution of known causes of HCC or proper ethnical differences remain to be elucidated. Nevertheless, these clearly different patterns are relevant to regional or worldwide clinical trial design. If this information is neglected by sponsors and researchers the rate of failure in HCC trials will not improve.
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Affiliation(s)
- Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
| | - Marta Mendiola
- Cancer Molecular Pathology and Therapeutic Targets Research Group, IdiPAZ, La Paz University Hospital, Madrid, Spain
| | - Jorge Barriuso
- Faculty of Life Sciences, University of Manchester, Manchester, UK.
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Drug delivery system targeting advanced hepatocellular carcinoma: Current and future. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2016; 12:853-869. [PMID: 26772424 DOI: 10.1016/j.nano.2015.12.381] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/20/2015] [Revised: 12/16/2015] [Accepted: 12/22/2015] [Indexed: 12/21/2022]
Abstract
UNLABELLED Hepatocellular carcinoma (HCC) has a fairly high morbidity and is notoriously difficult to treat due to long latent period before detection, multidrug resistance and severe drug-related adverse effects from chemotherapy. Targeted drug delivery systems (DDS) that can selectively deliver therapeutic drugs into tumor sites have demonstrated a great potential in cancer treatment, which could be utilized to resolve the limitations of conventional chemotherapy. Numerous preclinical studies of DDS have been published, but targeted DDS for HCC has yet to be made for practical clinical use. Since rational targeted DDS design should take cancer-specific properties into consideration, we have reviewed the biological and physicochemical properties of HCC extensively to provide a comprehensive understanding on HCC, and recent DDS studies on HCC, aiming to find some potential targeted DDSs for HCC treatment and a meaningful platform for further development of HCC treatments. FROM THE CLINICAL EDITOR Hepatocellular carcinoma has a high incidence worldwide and is known to be multidrug resistant. Thus, intensive research is being carried out to find better chemotherapeutic agents as well as new drug delivery systems. In this article, the authors reviewed in depth the current challenges facing new drug designs and also outlined novel targeted drug delivery systems (DDS) in the fight against HCC.
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Sanoff HK, Kim R, Ivanova A, Alistar A, McRee AJ, O'Neil BH. Everolimus and pasireotide for advanced and metastatic hepatocellular carcinoma. Invest New Drugs 2015; 33:505-9. [PMID: 25613083 DOI: 10.1007/s10637-015-0209-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Accepted: 01/13/2015] [Indexed: 12/17/2022]
Abstract
PURPOSE Few treatment options are available for patients with advanced or metastatic hepatocellular carcinoma (HCC). Based on preclinical and early clinical efficacy signals and lack of overlapping toxicity, we undertook this multicenter phase II trial to estimate efficacy and safety of everolimus and pasireotide in advanced HCC. METHODS Patients with advanced HCC not amenable to locoregional therapy and Child-Pugh A cirrhosis received everolimus 7.5 mg PO daily and pasireotide LAR 60 mg IM every 28 days. The primary endpoint was time to progression (TTP), with 26 events needed to evaluate if everolimus + pasireotide improved TTP from 2.8 to 4.4 months, with 80% power and an alpha of 0.05. Secondary endpoints included response as measured by RECIST modified for HCC, treatment-emergent adverse events, and overall survival. RESULTS After 24 patients were enrolled, results of a randomized trial showing no benefit of everolimus in HCC were released prompting an unplanned interim analysis that found the conditional probability of rejecting the null hypothesis based on events in those patients was 0.08. Therefore accrual was halted. Patients had a median age of 59 years, 21 (88%) had BCLC stage C cancer, and 11 (46%) metastatic disease. Median TTP was 3.5 months (95% CI 2-5.8) and median survival 6.7 months (95% CI 6-infinity). Best response was stable disease in ten patients. Grade 3 hyperglycemia occurred in 6 (25%). There were no grade 4 treatment-emergent events. CONCLUSION Despite promising early efficacy signals, we found no benefit for the combination of everolimus and pasireotide in HCC.
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Affiliation(s)
- Hanna K Sanoff
- Division of Hematology and Oncology, University of North Carolina at Chapel Hill, 170 Manning Drive, CB 7305, Chapel Hill, NC, 27599, USA,
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Pivonello C, De Martino MC, Negri M, Cuomo G, Cariati F, Izzo F, Colao A, Pivonello R. The GH-IGF-SST system in hepatocellular carcinoma: biological and molecular pathogenetic mechanisms and therapeutic targets. Infect Agent Cancer 2014; 9:27. [PMID: 25225571 PMCID: PMC4164328 DOI: 10.1186/1750-9378-9-27] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2012] [Accepted: 06/23/2014] [Indexed: 12/15/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide. Different signalling pathways have been identified to be implicated in the pathogenesis of HCC; among these, GH, IGF and somatostatin (SST) pathways have emerged as some of the major pathways implicated in the development of HCC. Physiologically, GH-IGF-SST system plays a crucial role in liver growth and development since GH induces IGF1 and IGF2 secretion and the expression of their receptors, involved in hepatocytes cell proliferation, differentiation and metabolism. On the other hand, somatostatin receptors (SSTRs) are exclusively present on the biliary tract. Importantly, the GH-IGF-SST system components have been indicated as regulators of hepatocarcinogenesis. Reduction of GH binding affinity to GH receptor, decreased serum IGF1 and increased serum IGF2 production, overexpression of IGF1 receptor, loss of function of IGF2 receptor and appearance of SSTRs are frequently observed in human HCC. In particular, recently, many studies have evaluated the correlation between increased levels of IGF1 receptors and liver diseases and the oncogenic role of IGF2 and its involvement in angiogenesis, migration and, consequently, in tumour progression. SST directly or indirectly influences tumour growth and development through the inhibition of cell proliferation and secretion and induction of apoptosis, even though SST role in hepatocarcinogenesis is still opened to argument. This review addresses the present evidences suggesting a role of the GH-IGF-SST system in the development and progression of HCC, and describes the therapeutic perspectives, based on the targeting of GH-IGF-SST system, which have been hypothesised and experimented in HCC.
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Affiliation(s)
- Claudia Pivonello
- Dipartimento di Medicina Clinica e Chirurgia, Università Federico II di Napoli, Via Sergio Pansini, 5, Naples 80131, Italy
| | - Maria Cristina De Martino
- Dipartimento di Medicina Clinica e Chirurgia, Università Federico II di Napoli, Via Sergio Pansini, 5, Naples 80131, Italy
| | - Mariarosaria Negri
- Dipartimento di Medicina Clinica e Chirurgia, Università Federico II di Napoli, Via Sergio Pansini, 5, Naples 80131, Italy
| | | | - Federica Cariati
- Dipartimento di Medicina Clinica e Chirurgia, Università Federico II di Napoli, Via Sergio Pansini, 5, Naples 80131, Italy
| | - Francesco Izzo
- National Cancer Institute G Pascale Foundation, Naples, Italy
| | - Annamaria Colao
- Dipartimento di Medicina Clinica e Chirurgia, Università Federico II di Napoli, Via Sergio Pansini, 5, Naples 80131, Italy
| | - Rosario Pivonello
- Dipartimento di Medicina Clinica e Chirurgia, Università Federico II di Napoli, Via Sergio Pansini, 5, Naples 80131, Italy
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Sollini M, Erba PA, Fraternali A, Casali M, Di Paolo ML, Froio A, Frasoldati A, Versari A. PET and PET/CT with 68gallium-labeled somatostatin analogues in Non GEP-NETs Tumors. ScientificWorldJournal 2014; 2014:194123. [PMID: 24693229 PMCID: PMC3947736 DOI: 10.1155/2014/194123] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2013] [Accepted: 10/30/2013] [Indexed: 12/27/2022] Open
Abstract
Somatostatin (SST) is a 28-amino-acid cyclic neuropeptide mainly secreted by neurons and endocrine cells. A major interest for SST receptors (SSTR) as target for in vivo diagnostic and therapeutic purposes was born since a series of stable synthetic SST-analouges PET became available, being the native somatostatin non feasible for clinical use due to the very low metabolic stability. The rationale for the employment of SST-analogues to image cancer is both based on the expression of SSTR by tumor and on the high affinity of these compounds for SSTR. The primary indication of SST-analogues imaging is for neuroendocrine tumors (NETs), which usually express a high density of SSTR, so they can be effectively targeted and visualized with radiolabeled SST-analogues in vivo. Particularly, SST-analogues imaging has been widely employed in gastroenteropancreatic (GEP) NETs. Nevertheless, a variety of tumors other than NETs expresses SSTR thus SST-analogues imaging can also be used in these tumors, particularly if treatment with radiolabeled therapeutic SST-analouges PET is being considered. The aim of this paper is to provide a concise overview of the role of positron emission tomography/computed tomography (PET/CT) with (68)Ga-radiolabeled SST-analouges PET in tumors other than GEP-NETs.
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Affiliation(s)
- Martina Sollini
- Nuclear Medicine Unit, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, 42123 Reggio Emilia, Italy
| | - Paola Anna Erba
- Regional Center of Nuclear Medicine, University of Pisa, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, 56125 Pisa, Italy
| | - Alessandro Fraternali
- Nuclear Medicine Unit, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, 42123 Reggio Emilia, Italy
| | - Massimiliano Casali
- Nuclear Medicine Unit, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, 42123 Reggio Emilia, Italy
| | - Maria Liberata Di Paolo
- Nuclear Medicine Unit, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, 42123 Reggio Emilia, Italy
| | - Armando Froio
- Nuclear Medicine Unit, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, 42123 Reggio Emilia, Italy
| | - Andrea Frasoldati
- Endocrinology Unit, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, 42123 Reggio Emilia, Italy
| | - Annibale Versari
- Nuclear Medicine Unit, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, 42123 Reggio Emilia, Italy
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Abdel-Rahman O, Lamarca A, Valle JW, Hubner RA. Somatostatin receptor expression in hepatocellular carcinoma: prognostic and therapeutic considerations. Endocr Relat Cancer 2014; 21:R485-93. [PMID: 25336571 DOI: 10.1530/erc-14-0389] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Sorafenib is the only systemic therapy to demonstrate a significant survival benefit over supportive care in robust randomised controlled trials for advanced hepatocellular carcinoma (HCC). In the context of an intense search for prognostic and predictive factors for response and efficacy of different systemic therapies (including sorafenib), a number of molecular targets have been identified, paving new avenues for potential therapeutic opportunities. Such molecular targets include somatostatin receptor (SSTR)-related alterations. In this review, we provide an overview of the various considerations relating to SSTRs as potentially novel prognostic and predictive biomarkers for HCC with special emphasis on the therapeutic potential of somatostatin analogues in HCC management.
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Affiliation(s)
- Omar Abdel-Rahman
- Clinical Oncology DepartmentFaculty of Medicine, Ain Shams University, Cairo, EgyptDepartment of Medical OncologyThe Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UKUniversity of ManchesterManchester Academic Health Sciences Centre (MAHSC), Manchester, UK
| | - Angela Lamarca
- Clinical Oncology DepartmentFaculty of Medicine, Ain Shams University, Cairo, EgyptDepartment of Medical OncologyThe Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UKUniversity of ManchesterManchester Academic Health Sciences Centre (MAHSC), Manchester, UK
| | - Juan W Valle
- Clinical Oncology DepartmentFaculty of Medicine, Ain Shams University, Cairo, EgyptDepartment of Medical OncologyThe Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UKUniversity of ManchesterManchester Academic Health Sciences Centre (MAHSC), Manchester, UK Clinical Oncology DepartmentFaculty of Medicine, Ain Shams University, Cairo, EgyptDepartment of Medical OncologyThe Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UKUniversity of ManchesterManchester Academic Health Sciences Centre (MAHSC), Manchester, UK
| | - Richard A Hubner
- Clinical Oncology DepartmentFaculty of Medicine, Ain Shams University, Cairo, EgyptDepartment of Medical OncologyThe Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UKUniversity of ManchesterManchester Academic Health Sciences Centre (MAHSC), Manchester, UK
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Theodoropoulou M, Stalla GK. Somatostatin receptors: from signaling to clinical practice. Front Neuroendocrinol 2013; 34:228-52. [PMID: 23872332 DOI: 10.1016/j.yfrne.2013.07.005] [Citation(s) in RCA: 276] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2013] [Revised: 06/13/2013] [Accepted: 07/12/2013] [Indexed: 02/08/2023]
Abstract
Somatostatin is a peptide with a potent and broad antisecretory action, which makes it an invaluable drug target for the pharmacological management of pituitary adenomas and neuroendocrine tumors. Somatostatin receptors (SSTR1, 2A and B, 3, 4 and 5) belong to the G protein coupled receptor family and have a wide expression pattern in both normal tissues and solid tumors. Investigating the function of each SSTR in several tumor types has provided a wealth of information about the common but also distinct signaling cascades that suppress tumor cell proliferation, survival and angiogenesis. This provided the rationale for developing multireceptor-targeted somatostatin analogs and combination therapies with signaling-targeted agents such as inhibitors of the mammalian (or mechanistic) target of rapamycin (mTOR). The ability of SSTR to internalize and the development of rabiolabeled somatostatin analogs have improved the diagnosis and treatment of neuroendocrine tumors.
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Affiliation(s)
- Marily Theodoropoulou
- Department of Endocrinology, Max Planck Institute of Psychiatry, Kraepelinstrasse 10, 80804 Munich, Germany.
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Liu Y, Jiang L, Mu Y. Somatostatin receptor subtypes 2 and 5 are associated with better survival in operable hepatitis B-related hepatocellular carcinoma following octreotide long-acting release treatment. Oncol Lett 2013; 6:821-828. [PMID: 24137418 PMCID: PMC3789087 DOI: 10.3892/ol.2013.1435] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2012] [Accepted: 06/21/2013] [Indexed: 01/29/2023] Open
Abstract
Liver resections for hepatocellular carcinoma (HCC) in cirrhotic livers are associated with early recurrence and poor survival. Somatostatin analogues (SSAs) have been reported to inhibit cell proliferation by interacting with specific somatostatin receptors (SSTRs) 2 and 5. The present study investigated whether SSTR expression in HCC was associated with the clinical outcome following octreotide long-acting release (LAR) treatment. Paired tumor and cirrhotic liver samples were obtained following a liver resection from 99 patients with stage I-II HCC and HBV-related cirrhosis. The expression of SSTR2 and 5 was assessed using quantitative (q)PCR and immunohistochemistry. The patients were classified into two groups, the high expression (n=47) and low expression (n=52) groups, based on the gene expression levels. The clinicopathological data and survival results of the two groups were compared. When compared with the surrounding cirrhotic tissue, the SSTR2 and 5 mRNA levels were significantly decreased in the HCC tissue. There were no significant differences between the groups with respect to the baseline characteristics. The tumor recurrence rate was significantly lower in the high expression group compared with that of the low expression group (63.83% vs. 82.69%; P=0.033). The 1-, 3- and 5-year disease-free and overall survival rates of the high expression group were 97, 89 and 71% and 98, 89 and 74%, respectively. The survival time of the members of the high expression group was longer compared with that of the low expression group. The multivariate analysis revealed that the TNM-7 stage and SSTR2 expression were independent prognostic factors for survival. In conclusion, SSTR mRNA expression correlated with survival in patients with early-stage hepatitis B virus (HBV)-related HCC who were treated with octreotide LAR following surgery. The inhibitory effects of SSAs on tumor growth may be mediated by SSTR expression.
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Affiliation(s)
- Yao Liu
- Department of Pediatric Surgery, National Center for Cardiovascular Disease and Fuwei Hospital, Chinese Acadamy of Medical Sciences, Peking Union Medical College, Beijing 100037, P.R. China
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Peptide receptor targeting in cancer: the somatostatin paradigm. INTERNATIONAL JOURNAL OF PEPTIDES 2013; 2013:926295. [PMID: 23476673 PMCID: PMC3582104 DOI: 10.1155/2013/926295] [Citation(s) in RCA: 87] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/29/2012] [Revised: 12/10/2012] [Accepted: 12/28/2012] [Indexed: 02/06/2023]
Abstract
Peptide receptors involved in pathophysiological processes represent promising therapeutic targets. Neuropeptide somatostatin (SST) is produced by specialized cells in a large number of human organs and tissues. SST primarily acts as inhibitor of endocrine and exocrine secretion via the activation of five G-protein-coupled receptors, named sst1–5, while in central nervous system, SST acts as a neurotransmitter/neuromodulator, regulating locomotory and cognitive functions. Critical points of SST/SST receptor biology, such as signaling pathways of individual receptor subtypes, homo- and heterodimerization, trafficking, and cross-talk with growth factor receptors, have been extensively studied, although functions associated with several pathological conditions, including cancer, are still not completely unraveled. Importantly, SST exerts antiproliferative and antiangiogenic effects on cancer cells in vitro, and on experimental tumors in vivo. Moreover, SST agonists are clinically effective as antitumor agents for pituitary adenomas and gastro-pancreatic neuroendocrine tumors. However, SST receptors being expressed by tumor cells of various tumor histotypes, their pharmacological use is potentially extendible to other cancer types, although to date no significant results have been obtained. In this paper the most recent findings on the expression and functional roles of SST and SST receptors in tumor cells are discussed.
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Hasskarl J, Kaufmann M, Schmid HA. Somatostatin receptors in non-neuroendocrine malignancies: the potential role of somatostatin analogs in solid tumors. Future Oncol 2011; 7:895-913. [PMID: 21732759 DOI: 10.2217/fon.11.66] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Somatostatin receptors (sstrs) are G-protein-coupled receptors that mediate various physiological effects when activated by the neuropeptide somatostatin or its synthetic analogs. In addition to the well-documented antisecretory effects of sstr2-preferential somatostatin analogs octreotide and lanreotide, ligand binding to sstr initiates an inhibitory action on tumor growth. This effect may result from both indirect actions (suppression of growth factors and growth-promoting hormones [e.g., GH/IGF-1 axis] and inhibition of angiogenesis) and direct actions (activation of antigrowth activities [e.g., apoptosis]). As solid tumor cells express multiple sstrs, there is a rationale to evaluate the potential antitumor effects of pasireotide (SOM230), a multireceptor-targeted somatostatin analog with high binding affinity for sstr1–3 and sstr5. Pasireotide reduces systemic IGF-1 levels more potently than currently available somatostatin analogs and has been well tolerated in clinical trials.
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Affiliation(s)
| | - Martina Kaufmann
- Novartis Pharma AG, Forum 1, Novartis Campus, CH-4056 Basel, Switzerland
| | - Herbert A Schmid
- Novartis Pharma AG, Forum 1, Novartis Campus, CH-4056 Basel, Switzerland
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Caraglia M, Giuberti G, Marra M, Addeo R, Montella L, Murolo M, Sperlongano P, Vincenzi B, Naviglio S, Prete SD, Abbruzzese A, Stiuso P. Oxidative stress and ERK1/2 phosphorylation as predictors of outcome in hepatocellular carcinoma patients treated with sorafenib plus octreotide LAR. Cell Death Dis 2011; 2:e150. [PMID: 21525937 PMCID: PMC3122065 DOI: 10.1038/cddis.2011.34] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
We reported a relevant activity of the combination between sorafenib and octreotide long-acting release (LAR) in advanced hepatocellular carcinoma (HCC) patients. In this work, we have studied if oxidative stress in both serum and peripheral blood mononuclear cells (PBMC) and pERK activation status in PBMC could be predictive of response. In the 20 responsive patients, the decrease of reactive oxygen species levels was already detectable after 10 days (T10) from the beginning of sorafenib administration, and this effect was enhanced by the combined treatment with sorafenib+octreotide LAR (T21). This effect correlated with the modulation of superoxide dismutase (SOD) activity (physiological scavenger of O(2-)) and of serum nitric oxide (NO) levels. Sorafenib alone induced an increase of about 40% of NO levels and of about two-fold of SOD activity in responsive patients, and both effects were significantly potentiated by the combined treatment. We found a gradual reduction of Erk1/2 activity, as evaluated by cytofluorimetric analysis, in 15 responsive patients reaching about 50% maximal decrease at T21. On the other hand, in 17 resistant patients, Erk1/2 activity was about 80% increased at T21. The determination of both the oxidative stress status and pERK activity in PBMC has high value in the prediction of response to sorafenib+octreotide therapy in HCC patients.
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Affiliation(s)
- M Caraglia
- Department of Biochemistry and Biophysics, Second University of Naples, Naples, Italy.
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Mutation of herpesvirus Saimiri ORF51 glycoprotein specifically targets infectivity to hepatocellular carcinoma cell lines. J Biomed Biotechnol 2010; 2011:785158. [PMID: 21197456 PMCID: PMC3004438 DOI: 10.1155/2011/785158] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2010] [Revised: 10/14/2010] [Accepted: 10/14/2010] [Indexed: 11/18/2022] Open
Abstract
Herpesvirus saimiri (HVS) is a gamma herpesvirus with several properties that make it an amenable gene therapy vector; namely its large packaging capacity, its ability to persist as a nonintegrated episome, and its ability to infect numerous human cell types. We used RecA-mediated recombination to develop an HVS vector with a mutated virion protein. The heparan sulphate-binding region of HVS ORF51 was substituted for a peptide sequence which interacts with somatostatin receptors (SSTRs), overexpressed on hepatocellular carcinoma (HCC) cells. HVS mORF51 showed reduced infectivity in non-HCC human cell lines compared to wild-type virus. Strikingly, HVS mORF51 retained its ability to infect HCC cell lines efficiently. However, neutralisation assays suggest that HVS mORF51 has no enhanced binding to SSTRs. Therefore, mutation of the ORF51 glycoprotein has specifically targeted HVS to HCC cell lines by reducing the infectivity of other cell types; however, the mechanism for this targeting is unknown.
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Ovadia O, Greenberg S, Laufer B, Gilon C, Hoffman A, Kessler H. Improvement of drug-like properties of peptides: the somatostatin paradigm. Expert Opin Drug Discov 2010; 5:655-71. [DOI: 10.1517/17460441.2010.493935] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Borbath I, Leclercq IA, Sempoux C, Abarca-Quinones J, Desaeger C, Horsmans Y. Efficacy of lanreotide in preventing the occurrence of chemically induced hepatocellular carcinoma in rats. Chem Biol Interact 2010; 183:238-48. [DOI: 10.1016/j.cbi.2009.10.011] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2009] [Revised: 10/01/2009] [Accepted: 10/16/2009] [Indexed: 12/26/2022]
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Dancygier H. Malignant Tumors. CLINICAL HEPATOLOGY 2010:1305-1350. [DOI: 10.1007/978-3-642-04519-6_48] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Schöniger-Hekele M, Kettenbach J, Peck-Radosavljevic M, Müller C. Octreotide treatment of patients with hepatocellular carcinoma--a retrospective single centre controlled study. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2009; 28:142. [PMID: 19887008 PMCID: PMC2779805 DOI: 10.1186/1756-9966-28-142] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/18/2009] [Accepted: 11/03/2009] [Indexed: 12/12/2022]
Abstract
Background Studies of treatment with octreotide of patients with hepatocellular carcinoma (HCC) gave conflicting results. We analyzed retrospectively the survival of our patients treated with octreotide monotherapy and compared it to stage-matched patients who received either TACE, multimodal therapy or palliative care. Methods 95 patients seen at the department of Gastroenterology and Hepatology, Medical University of Vienna with HCC in BCLC stage A or B, who received either TACE, multimodal therapy, long-acting octreotide or palliative care were reviewed for this retrospective study. Results Survival rates of patients with BCLC stage B and any "active" treatment (long-acting octreotide, TACE or multimodal therapy) were significantly higher (22.4, 22.0, 35.5 months) compared to patients who received palliative care only (2.9 months). Survival rates of patients with BCLC stage A and "active" treatment (31.4, 37.3, 40.2 months) compared to patients who received only palliative care (15.1 months) did not show statistically significant differences. Octreotide monotherapy showed a similar outcome compared to patients who received TACE or multimodal therapy. Conclusion Survival under octreotide treatment was not different compared to TACE or multimodal therapy and might be a therapeutic option for patients with HCC.
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Affiliation(s)
- Maximilian Schöniger-Hekele
- Universitätsklinik für Innere Medizin III, Klinische Abteilung für Gastroenterologie und Hepatologie, Medical University of Vienna, Vienna, Austria.
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Kerros C, Cavey T, Sola B, Jauzac P, Allouche S. Somatostatin and opioid receptors do not regulate proliferation or apoptosis of the human multiple myeloma U266 cells. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2009; 28:77. [PMID: 19500423 PMCID: PMC2698864 DOI: 10.1186/1756-9966-28-77] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/21/2009] [Accepted: 06/07/2009] [Indexed: 12/12/2022]
Abstract
BACKGROUND opioid and somatostatin receptors (SSTRs) that can assemble as heterodimer were individually reported to modulate malignant cell proliferation and to favour apoptosis. MATERIALS AND METHODS SSTRs and opioid receptors expression were examined by RT-PCR, western-blot and binding assays, cell proliferation was studied by XTT assay and propidium iodide (PI) staining and apoptosis by annexin V-PI labelling. RESULTS almost all human malignant haematological cell lines studied here expressed the five SSTRs. Further experiments were conducted on the human U266 multiple myeloma cells, which express also micro-opioid receptors (MOP-R). XTT assays and cell cycle studies provide no evidence for a significant effect upon opioid or somatostatin receptors stimulation. Furthermore, neither direct effect nor potentiation of the Fas-receptor pathway was detected on apoptosis after these treatments. CONCLUSION these data suggest that SSTRs or opioid receptors expression is not a guaranty for an anti-tumoral action in U266 cell line.
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Affiliation(s)
- Céline Kerros
- Laboratoire de biologie moléculaire et cellulaire de la signalisation, UPRES-EA 3919, IFR 146 ICORE, Université de Caen, Caen, France.
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AZAD A, CHIONH F, CEBON J. Targeted agents for the systemic treatment of advanced hepatocellular carcinoma. Asia Pac J Clin Oncol 2009. [DOI: 10.1111/j.1743-7563.2009.01202.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
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Samonakis DN, Notas G, Christodoulakis N, Kouroumalis EA. Mechanisms of action and resistance of somatostatin analogues for the treatment of hepatocellular carcinoma: a message not well taken. Dig Dis Sci 2008; 53:2359-65. [PMID: 18273705 DOI: 10.1007/s10620-007-0175-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2007] [Accepted: 12/20/2007] [Indexed: 02/08/2023]
Abstract
Somatostatin (SST) acts as an inhibitory peptide of various secretory and proliferative processes. Apart from neuroendocrine tumors, where SST analogues have an established role, they have been tested in other tumors such as hepatocellular carcinoma (HCC) in the view of the fact that chemotherapy is not working. Several positive reports have been published. Approximately 40% of patients respond with improved survival and an impressive quality of life. A usual misunderstanding in trial designs is that, although SST is not a rescue drug, selection of patients is inappropriate, with mostly moribund patients being recruited. SST analogues do not seem to work in 60% of HCCs and this has been linked to the presence of SST receptors (SSTR) in the tumor, while several resistance mechanisms might be involved. Future management should engage more specific SST analogues targeted to a tumor with a known SSTR map. The use of somatostatin analogues as an adjunct therapy in combination with other treatment modalities should also be investigated.
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Affiliation(s)
- Dimitrios N Samonakis
- Department of Gastroenterology & Hepatology, University Hospital of Heraklion, Heraklion, Crete, Greece.
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37
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Therapy of experimental hepatic cancers with cytotoxic peptide analogs targeted to receptors for luteinizing hormone-releasing hormone, somatostatin or bombesin. Anticancer Drugs 2008; 19:349-58. [DOI: 10.1097/cad.0b013e3282f9adce] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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38
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Borbath I, Leclercq IA, Abarca-Quinones J, Desaeger C, Lebrun V, Moulin P, Sempoux C, Horsmans Y. Inhibition of early preneoplastic events in the rat liver by the somatostatin analog lanreotide. Cancer Sci 2007; 98:1831-9. [PMID: 17900309 PMCID: PMC11158449 DOI: 10.1111/j.1349-7006.2007.00626.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2007] [Revised: 08/16/2007] [Accepted: 08/21/2007] [Indexed: 12/21/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death, and its incidence is increasing worldwide. Due to the known risk factors (mainly hepatitis B and C viruses), we believe there is a rationale for a chemopreventive approach to treat HCC. Here, based on described in vitro data, we evaluated the preventive effects of lanreotide, a somatostatin analog, on the induction of early carcinogenic events. We monitored preneoplastic foci induced by a two-stage initiation/promotion model of hepatocarcinogenesis in male Wistar rats, using diethylnitrosamine and 2-acetylaminofluorene. Lanreotide was given starting the day after the first diethylnitrosamine injection. By quantitative morphometry, we showed that lanreotide significantly decreases the size of induced preneoplastic foci. Analysis of proliferation and apoptosis assessed by immunohistochemistry, showed decreased proliferation and increased cell death in rats treated with lanreotide. As these events were associated with a significant decreased expression of the cell cycle regulator cyclin D1 and an increased expression of the cyclin-dependent kinase inhibitor p27(kip1) compared to the non-treated group, it is tempting to speculate that these factors are involved in the favorable effect of lanreotide. In conclusion, lanreotide significantly decreases early carcinogenic transformation in a two-step rat model. As lanreotide has a low toxicity profile, we believe it would be interesting to evaluate its effect in chemoprevention of HCC.
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Affiliation(s)
- Ivan Borbath
- Gastroenterology Laboratory, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Avenue Hippocrate, 10, Brussels 1200, Belgium.
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39
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Dimitroulopoulos D, Xinopoulos D, Tsamakidis K, Zisimopoulos A, Andriotis E, Panagiotakos D, Fotopoulou A, Chrysohoou C, Bazinis A, Daskalopoulou D, Paraskevas E. Long acting octreotide in the treatment of advanced hepatocellular cancer and overexpression of somatostatin receptors: randomized placebo-controlled trial. World J Gastroenterol 2007. [PMID: 17589893 DOI: 10.3748/wjg.v13.i13.3164] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To estimate if and to what extent long acting octreotide (LAR) improves survival and quality of life in patients with advanced hepatocellular carcinoma (HCC). METHODS A total of 127 cirrhotics, stages A-B, due to chronic viral infections and with advanced HCC, were enrolled in the study. Scintigraphy with 111Indium labeled octreotide was performed in all cases. The patients with increased accumulation of radionuclear compound were randomized to receive either oral placebo only or octreotide/octreotide LAR only as follows: octreotide 0.5 mg s.c. every 8 h for 6 wk, at the end of wk 4-8 octreotide LAR 20 mg i.m. and at the end of wk 12 and every 4 wk octreotide LAR 30 mg i.m.. Follow-up was worked out monthly as well as the estimation of quality of life (QLQ-C30 questionnaire). Patients with negative somatostatin receptors (SSTR) detection were followed up in the same manner. RESULTS Scintigraphy demonstrated SSTR in 61 patients. Thirty were randomized to receive only placebo and 31 only octreotide. A significantly higher survival time was observed for the octreotide group (49+/-6 wk) as compared to the control group (28+/-1 wk) and to the SSTR negative group (28+/-2 wk), LR=20.39, df=2, P<0.01. The octreotide group presented 68.5% lower hazard ratio [95% CI (47.4%-81.2%)]. During the first year, a 22%, 39% and 43% decrease in the QLQ-C30 score was observed in each group, respectively. CONCLUSION The proposed therapeutic approach has shown to improve the survival and quality of life in SSTR positive patients with advanced HCC.
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Affiliation(s)
- D Dimitroulopoulos
- Liver Cancer Unit, Agios Savvas Cancer Hospital, 35 Parnassou str., GR-152 34 Halandri-Athens, and Laboratory of Biostatistics, Department of Nursing, University of Athens, Greece.
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40
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Verset G, Verslype C, Reynaert H, Borbath I, Langlet P, Vandebroek A, Peeters M, Houbiers G, Francque S, Arvanitakis M, Van Laethem JL. Efficacy of the combination of long-acting release octreotide and tamoxifen in patients with advanced hepatocellular carcinoma: a randomised multicentre phase III study. Br J Cancer 2007; 97:582-8. [PMID: 17687341 PMCID: PMC2360361 DOI: 10.1038/sj.bjc.6603901] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
To assess the efficacy of the combination of long-acting release (LAR) octreotide and tamoxifen (TMX) for the treatment of advanced hepatocellular carcinoma (HCC). A total of 109 patients with advanced HCC were randomised to receive octreotide LAR combined with TMX (n=56) (experimental treatment group) or TMX alone (n=53; control group). The clinical, biological and tumoural parameters were recorded every 3 months until death. Primary end point was patient survival; secondary end points were the impact of therapy on tumour response, quality of life and variceal bleeding episodes. Univariate and multivariate analyses were performed for assessment of specific prognostic factors. The median survival was 3 months (95% CI 1.4-4.6) for the experimental treatment group and 6 months (CI 95% 2-10) for the control group (P=0.609). There was no difference in terms of alpha-foetoprotein (alpha-FP) decrease, tumour regression, improvement of quality of life and prevention of variceal bleeding between the two groups. Variables associated with a better survival in the multivariate analysis were: presence of cirrhosis, alpha-FP level <400 ng ml(-1) and Okuda stage I. The combination of octreotide LAR and TMX does not influence survival, tumour progression or quality of life in patients with advanced HCC.
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Affiliation(s)
- G Verset
- Erasme University Hospital, ULB, Brussels, Belgium.
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41
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Dimitroulopoulos D, Xinopoulos D, Tsamakidis K, Zisimopoulos A, Andriotis E, Panagiotakos D, Fotopoulou A, Chrysohoou C, Bazinis A, Daskalopoulou D, Paraskevas E. Long acting octreotide in the treatment of advanced hepatocellular cancer and overexpression of somatostatin receptors: Randomized placebo-controlled trial. World J Gastroenterol 2007; 13:3164-70. [PMID: 17589893 PMCID: PMC4436600 DOI: 10.3748/wjg.v13.i23.3164] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To estimate if and to what extent long acting octreotide (LAR) improves survival and quality of life in patients with advanced hepatocellular carcinoma (HCC).
METHODS: A total of 127 cirrhotics, stages A-B, due to chronic viral infections and with advanced HCC, were enrolled in the study. Scintigraphy with 111Indium labeled octreotide was performed in all cases. The patients with increased accumulation of radionuclear compound were randomized to receive either oral placebo only or octreotide/octreotide LAR only as follows: octreotide 0.5mg s.c. every 8 h for 6 wk, at the end of wk 4-8 octreotide LAR 20 mg i.m. and at the end of wk 12 and every 4 wk octreotide LAR 30mg i.m.. Follow-up was worked out monthly as well as the estimation of quality of life (QLQ-C30 questionnaire). Patients with negative somatostatin receptors (SSTR) detection were followed up in the same manner.
RESULTS: Scintigraphy demonstrated SSTR in 61 patients. Thirty were randomized to receive only placebo and 31 only octreotide. A significantly higher survival time was observed for the octreotide group (49 ± 6 wk) as compared to the control group (28 ± 1 wk) and to the SSTR negative group (28 ± 2 wk), LR = 20.39, df = 2, P < 0.01. The octreotide group presented 68.5% lower hazard ratio [95% CI (47.4%-81.2%)]. During the first year, a 22%, 39% and 43% decrease in the QLQ-C30 score was observed in each group respectively.
CONCLUSION: The proposed therapeutic approach has shown to improve the survival and quality of life in SSTR positive patients with advanced HCC.
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Affiliation(s)
- D Dimitroulopoulos
- Liver Cancer Unit, Agios Savvas Cancer Hospital, 35 Parnassou str., GR-152 34 Halandri-Athens, and Laboratory of Biostatistics, Department of Nursing, University of Athens, Greece.
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42
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Abstract
In the absence of large randomized trials, the current treatment strategy for hepatocellular carcinoma (HCC) remains a matter of choice depending mostly on retrospective studies, experience of centers, and the technical therapeutic possibilities. In fact, treatment decisions must be based on HCC extension and liver function, which is dependent on underlying liver disease. Cirrhosis limits therapeutic choices, life expectancy, and tolerance to therapy. Surgical resection and/or local destruction are the most common curative treatments. Orthotopic liver transplantation is probably the best treatment for small HCC developed in cirrhosis because it treats tumor, cirrhosis, and preneoplastic lesions at the same time. However, this treatment method is feasible in fewer than 5% of cases. Adjuvant treatments include transarterial chemoembolization, chemotherapy, polyprenoic acid, interferon, adoptive immunotherapy, and intra-arterial radioactive lipiodol. Results from trials warrant confirmation in larger randomized trials to show a clear survival benefit on recurrence rate, secondary prevention, and overall survival. Chemoembolization is the only palliative treatment that has been proven to be active, unlike systemic chemotherapy, immunotherapy, and hormone therapy, whose activity is largely questionable and must all be restricted to clinical trials. Possible future therapeutic strategies include epidermal growth factor receptor inhibitors, antivascular endothelial growth factor therapies, cyclin D inhibitors, and HMG-CoA reductase inhibitors.
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Affiliation(s)
- Philippe Rougier
- Service d'Hépato-gastroentérologie, Hopital Ambroise Paré, 92100 Boulogne, France.
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Affiliation(s)
- F Farinati
- Department of Surgical and Gastroenterological Sciences, Venetian Institute of Oncology (IOV), Padua University, Padua, Italy
- E-mail:
| | - A Sergio
- Department of Surgical and Gastroenterological Sciences, Venetian Institute of Oncology (IOV), Padua University, Padua, Italy
| | - A Baldan
- Department of Surgical and Gastroenterological Sciences, Venetian Institute of Oncology (IOV), Padua University, Padua, Italy
| | - P Zucchetta
- Department of Diagnostic Medical Sciences, Padua University, Padua, Italy
| | - V D Corleto
- Department of Digestive and Liver Diseases, II School of Medicine, University ‘La Sapienza’, Rome, Italy
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44
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Taieb J, Barbare JC, Rougier P. Medical treatments for hepatocellular carcinoma (HCC): what’s next? Ann Oncol 2006; 17 Suppl 10:x308-14. [PMID: 17018744 DOI: 10.1093/annonc/mdl279] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Affiliation(s)
- J Taieb
- Service d'Hépato-gastroentérologie, Groupe Hospitalier Pitié Salpétrière, Paris, France
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45
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Treiber G, Wex T, Röcken C, Fostitsch P, Malfertheiner P. Impact of biomarkers on disease survival and progression in patients treated with octreotide for advanced hepatocellular carcinoma. J Cancer Res Clin Oncol 2006; 132:699-708. [PMID: 16835748 DOI: 10.1007/s00432-006-0118-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2005] [Accepted: 05/04/2006] [Indexed: 01/05/2023]
Abstract
BACKGROUND Current determination of prognosis for advanced hepatocellular carcinoma (HCC) is mainly based on clinical assessment. We aimed to determine the impact of biomarkers as predictive factors for HCC progression and survival during octreotide-based treatments. PATIENTS AND METHODS We included patients who had been prospectively randomised to receive either octreotide (30 mg) alone monthly (n = 39) or in combination with rofecoxib (up to 50 mg bid daily, n = 32) for a minimum of 6 months, or until death occurred. RESULTS Overall median survival (154 days) and median time to progression (94 days) were not different for both treatments and the biomarkers investigated (VEGF-A, IGF-1, PGE-2, ET-A) were similarly distributed amongst treatment groups. Combined univariate group analysis revealed that survival was decreased for an uptake ratio of > 2 on initial octreoscan (P = 0.05); baseline serum VEGF-A and IGF-1 were further significantly associated with survival. On multivariate analysis, uncorrected serum VEGF-A appeared to be the most significant predictor for tumor progression and survival. CONCLUSIONS Biomarkers, in addition to established tumor markers, are independent predictors of tumor progression and survival in patients with advanced HCC treated with octreotide. Furthermore, the involvement of VEGF-A implies the inhibition of angiogenesis as a potential mechanism of action for this drug.
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Affiliation(s)
- G Treiber
- Department of Gastroenterology and Hepatology, University Hospital of Magdeburg, Magdeburg, Germany.
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46
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Samonakis DN, Christodoulakis N, Kouroumalis EA. Octreotide for unresectable hepatocellular carcinoma: beyond the first sight. J Clin Gastroenterol 2006; 40:86-7. [PMID: 16340641 DOI: 10.1097/01.mcg.0000190778.50279.26] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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47
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Plentz RR, Tillmann HL, Kubicka S, Bleck JS, Gebel M, Manns MP, Rudolph KL. Hepatocellular carcinoma and octreotide: treatment results in prospectively assigned patients with advanced tumor and cirrhosis stage. J Gastroenterol Hepatol 2005; 20:1422-8. [PMID: 16105131 DOI: 10.1111/j.1440-1746.2005.03959.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM Treatment of inoperable hepatocellular carcinoma (HCC) remains a major clinical problem. The only efficient treatment options are percutaneous ethanol injection (PEI), radiofrequency ablation (RF) and transarterial chemoembolization (TACE), but these therapies are only applicable to patients with limited tumor spread and sufficient liver function. For patients with advanced tumor and poor liver function a systemic therapy is required. Octreotide, a somatostatin analog with antimitotic activity, is a controversial treatment option. METHODS In the current study we prospectively assigned a group of 41 HCC patients with advanced HCC and cirrhosis stage to treatment with octreotide. The clinical and laboratory parameters were monitored and survival was analyzed using a Cox regression model. RESULTS The medium survival in the group of all patients was 571 days. Using the Cox regression there was a significant difference in survival for alpha-fetoprotein (P = 0.026) and Quick's test (P = 0.009) in consideration of the tumor dimension compared to the other characteristics. The tumor remained stable in 26 patients over a mean follow-up of 21 months and progressed in 14 patients. One patient showed a partial response. There was no incidence of severe side-effects (WHO grade 3-4). During the follow-up time, 14 patients died because of their underlying disease. CONCLUSIONS Treatment with octreotide appears safe and patients show similar survival compared to a group of patients with advanced HCC treated with TACE. Further studies are necessary to investigate somatostatin receptor subtypes or receptor mutations of patients with advanced HCC in relation to their response.
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Affiliation(s)
- Ruben R Plentz
- Department of Gastroenterology, Hepatology and Endocrinology, Medical School of Hannover, Germany
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48
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Lasfer M, Vadrot N, Schally AV, Nagy A, Halmos G, Pessayre D, Feldmann G, Reyl-Desmars FJ. Potent induction of apoptosis in human hepatoma cell lines by targeted cytotoxic somatostatin analogue AN-238. J Hepatol 2005; 42:230-7. [PMID: 15664249 DOI: 10.1016/j.jhep.2004.10.014] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2004] [Revised: 10/01/2004] [Accepted: 10/26/2004] [Indexed: 01/24/2023]
Abstract
BACKGROUND/AIMS The efficacy of a targeted cytotoxic hybrid somatostatin analogue AN-238 and of its superactive radical 2-pyrrolinodoxorubicin (AN-201) to induce apoptosis of HepG2 and Hep3B human hepatoma cell lines were studied. AN-238 was designed to selectively target tumor cells expressing somatostatin receptor subtypes (sst(s)). Its effects on HepG2 or Hep3B cells displaying or lacking tumor suppressor p53, respectively, were compared. Normal rat isolated hepatocytes were also tested. METHODS sst(s) were characterized by binding assays and RT-PCR. Cytotoxicity was quantified by flow cytometry. DNA fragmentation was studied by gel electrophoresis, PARP cleavage by Western blot and ROS formation using fluorescent probes. RESULTS Specific binding of iodinated RC-160 to HepG2 and Hep3B cells, and its displacement by AN-238 was characterized. mRNA for hsst(2A) was found in both cell lines. Flow cytometry showed a stronger effect of AN-238 than AN-201 to induce sub-G1 phase. DNA fragmentation, nuclear bodies, and PARP cleavage were observed. In addition, AN-238 increased formation of ROS more potently than AN-201. However, no inductions of DNA fragmentation by AN-201 or AN-238 were observed on rat hepatocytes. CONCLUSIONS Our results indicate that, in liver cancer, the cytotoxic somatostatin analogue AN-238 is a powerful agent that can induce apoptosis, through sst(s) and independently of p53.
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Affiliation(s)
- Malika Lasfer
- INSERM Unit 481, Faculté de Médecine Xavier Bichat, IFR 02, 16 rue Henri Huchard, BP 416, 75870 Paris Cedex 18, France
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